Substituted basic 2-aminotetralin in pharmaceuticals

ABSTRACT

For treatment of disorders of the central nervous system, the cardiovascular system or the intestinal tract, the new substituted basic 2-aminotetralins of the formula ##STR1## in which R 1  represents hydrogen or alkyl, 
     R 2  represents hydrogen, alkyl or acyl, and 
     R 3  represents quinuclidine or a group of the formula --(CH 2 ) a  --R 4 , --CH 2  --CH═CH--(CH 2 ) b  --R 4 , --CH 2  C.tbd.C--(CH 2 ) b  --R 4 , ##STR2## wherein a denotes a number from 1 to 10, 
     b denotes a number 0, 1, 2, 3 or 4, 
     c denotes a number 0, 1 or 2, 
     d denotes a number 2 or 3, and 
     x denotes oxygen, sulphur or NR 5 , 
     and their salts.

This is a division of application Ser. No. 130,373, filed Dec. 8, 1987,now U.S. Pat. No. 4,880,802 issued Apr. 14, 1989.

The invention relates to substituted basic 2-aminotetralins, processesfor their preparation, and their use in medicaments.

It is known, from EP-A1-41 488, that 2-aminotetralins which are mono- ordialkyl-substituted on the nitrogen act on the central nervous system.

It is likewise known [Biochem. Pharmacol. 34 (6), 883- 92] that2-(N-2'-chloropropyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride bonds irreversibly to various 5-HT receptor types.

In addition,2-(N-3-hydroxypropyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthaleneis known as an intermediate for the preparation of substances which acton the central nervous system [Eur. J. Pharm. 127, 67 81, 1986].

New substituted basic 2-aminotetralins of the general formula (I)##STR3## in which

R¹ represents hydrogen or alkyl,

R² represents hydrogen, alkyl or acyl, and

R³ represents quinuclidine or a group of the formula --(CH₂)_(a) --R⁴,--CH₂ --CH═CH--(CH₂)_(b) --R⁴, --CH₂ --C.tbd.C--(CH₂)_(b) --R⁴, ##STR4##wherein

a denotes a number from 1 to 10,

b denotes a number 0, 1, 2, 3 or 4,

c denotes a number 0, 1 or 2,

d denotes a number 2 or 3,

X denotes oxygen, sulphur or NR⁵,

where

R⁵ represents hydrogen or cycloalkyl, or represents alkyl which may besubstituted by halogen, hydroxyl, amino, alkylamino, dialkylamino,carbamoyl or sulphamoyl or, represents aryl, heteroaryl, aralkyl,alkoxycarbonyl, alkylsulphonyl, phenylsulphonyl, tolylsulphonyl,benzylsulphonyl, formyl, carbamoyl or sulphamoyl,

and

R⁴ denotes cyano or a group of the formula --OR⁶, --COOR⁷, --CONR⁸ R⁹,--SO₂ NR⁸ R⁹, --SO_(m) R¹⁰, --NR¹¹ R¹², ##STR5## where

c, d and X have the abovementioned meaning,

A represents hydrogen, alkylsulphonyl, phenylsulphonyl, tolylsulphonyl,benzylsulphonyl, acyl or alkoxycarbonyl,

R⁶ represents hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,tetrahydronapthalene-1-yl or benzothiadiazolyl,

R⁷ represents hydrogen, alkyl, alkenyl, aryl or aralkyl,

R⁸ and R⁹ are identical or different and represent hydrogen, alkyl, arylor aralkyl,

R¹⁰ represents alkyl, cycloalkyl, aryl or aralkyl, where the arylradicals may be up to trisubstituted, identically or differently, byhalogen, cyano, alkyl, alkoxy, trifluoromethyl or trifluoromethoxy, mrepresents a number 0, 1 or 2,

R¹¹ and R¹² are identical or different and represent hydrogen, alkyl,aryl or aralkyl, where the aryl radicals may be substituted by halogen,cyano, alkyl, alkoxy or trifluoromethyl, or

represent a group of the formula --COR¹³ or --SO₂₂ R¹⁴,

wherein

R¹³ denotes hydrogen, or an NHR¹⁵ group, or denotes alkyl or alkoxy, ordenotes aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, where theradicals mentioned may be up to trisubstituted, identically ordifferently, by alkyl, alkoxy, alkylthio, halogen, cyano,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino,alkylamino or dialkylamino,

R¹⁴ denotes cycloalkyl, or denotes alkyl which may be substituted bycyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, ordenotes aryl, aralkyl or heteroaryl, where the radicals mentioned may beup to trisubstituted, identically or differently, by alkyl, alkoxy,alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, amino, alkylamino or dialkylamino or denotes an NR⁸R⁹ group,

where

R⁸ and R⁹ have the abovementioned meaning and

R¹⁵ denotes hydrogen, or denotes cycloalkyl, or denotes alkyl which isoptionally substituted by cyano, halogen, trifluoromethyl ortrifluoromethoxy, or denotes aryl, aralkyl or heteroaryl where the arylradicals may be up to trisubstituted, identically or differently, byalkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, amino, alkylamino ordialkylamino,

or where

R¹¹ and R¹², together with the nitrogen atom, form a ring from theseries comprising ##STR6## wherein

n denotes a number 1 or 2,

or in which

R² and R³, together with the nitrogen atom, form a group of the formula##STR7## wherein

c and d have the abovementioned meaning, and

Y denotes oxygen, sulphur or a group of the formula NR⁵ or CH(CH₂)_(e)--NHR⁵,

where

R⁵ has the abovementioned meaning, and

e represents a number 0 to 4,

but where

R³ does not denote 3-hydroxypropyl when

R¹ represents methyl and R² represents propyl,

and where

R³ does not denote 2-methylthioethyl when

R¹ represents hydrogen or methyl and R² represents hydrogen, propyl orpropionyl,

and their salts have been found.

Surprisingly, the substances according to the invention display a goodaction on the central nervous system and can be used for therapeutictreatment of humans and animals.

The substances according to the invention have several asymmetricalcarbon atoms and can thus exist in various stereochemical forms. Inaddition, compounds having a sulphoxide group can likewise exist indifferent stereochemical forms. The invention relates both to theindividual isomers and to their mixtures. The following isomeric formsof the substituted basic 2-aminotetralins may be mentioned as examples:##STR8##

The substituted basic 2-aminotetralins according to the invention mayalso be present in the form of their salts. In general, salts withinorganic or organic acids may be mentioned here.

In the context of the present invention, physiologically acceptablesalts are preferred. Physiologically acceptable salts of the substitutedbasic 2-aminotetralines can be salts of the substances according to theinvention with mineral acids, carboxylic acids or sulphonic acids.Particularly preferred salts, for example, are those with hydrochloricacid, hydrobromic acid, sulphuric acid, phosphoric acid,methanesulphonic acid, ethanesulphonic acid, toluenesulphonic acid,benzenesulphonic acid, naphthalenedisulphonic acid, acetic acid,propionic acid, lactic acid, oxalic acid, malonic acid, succinic acid,maleic acid, fumaric acid, malic acid, tartaric acid, citric acid orbenzoic acid.

In general, alkyl represents a branched hydrocarbon radical having 1 to12 carbon atoms. Lower alkyl having 1 to about 6 carbon atoms ispreferred. Examples which may be mentioned are methyl, ethyl, propyl,isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl,isoheptyl, octyl and isooctyl.

In general, alkenyl represents a straight-chain or branched hydrocarbonradical having 2 to 12 carbon atoms and one or more, preferably one ortwo, double bonds. The lower alkyl radical having 2 to about 6 carbonatoms and one double bond is preferred. An alkenyl radical having 2 to 4carbon atoms and one double bond is particularly preferred. Exampleswhich maybe mentioned are allyl, propenyl, isopropenyl, butenyl,isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl, heptenyl,isoheptenyl, octentyl and isooctenyl.

In general, cycloalkyl represents a cyclic hydrocarbon radical having 5to 8 carbon atoms. The cyclopentane and the cyclohexane ring arepreferred. Examples which may be mentioned are cyclopentyl, cyclohexyl,cycloheptyl and cyclooctyl.

In general, aryl represents an aromatic radical having 6 to about 12carbon atoms. Preferred aryl radicals are phenyl, naphthyl and biphenyl.

In general, aralkyl represents an aryl radical, having 7 to 14 carbonatoms, which is bonded via an alkylene chain. Aralkyl radicals having 1to 6 carbon atoms in the ailphatic part and 6 to 12 carbon atoms in thearomatic part are preferred. Examples which may be mentioned are thefollowing aralkyl radicals: benzyl, naphthylmethyl, phenethyl andphenylpropyl.

In general, alkoxy represents a straight-chain or branched hydrocarbonradical, having 1 to 12 carbon atoms, which is bonded via an oxygenatom. Lower alkoxy having 1 to about 6 carbon atoms is preferred. Analkoxy radical having 1 to 4 carbon atoms is particularly preferred.Examples which may be mentioned are methoxy, ethoxy propoxy, isopropoxy,butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy, isohexoxy, heptoxy,isoheptoxy, octoxy or isooctoxy.

In general, aryloxy represents an aromatic radical, having 6 to about 12carbon atoms, which is bonded via an oxygen atom. Preferred aryloxyradicals are phenoxy or naphthyloxy.

In general, aralkoxy represents an aralkyl radical having 7 to 14 carbonatoms, the alkylene chain being bonded via an oxygen atom. Aralkoxyradicals having 1 to 6 carbon atoms in the aliphatic part and 6 to 12carbon atoms in the aromatic part are preferred. Examples which may bementioned are the following aralkoxy radicals: benzyloxy,naphthylmethoxy, phenethoxy and phentylpropyoxy.

In general, alkylthio represents a straight-chain or branchedhydrocarbon radical, having 1 to 12 carbon atoms, which is bonded via asulphur atom. Lower alkylthio having 1 to about 6 carbon atoms ispreferred. An alkylthio radical having 1 to 4 carbon atoms isparticularly preferred. Examples which maybe mentioned are methylthio,ethylthio, propylthio, isopropylthio, butylthio, isobutylthio,pentylthio, isopentylthio, hexylthio, isoxhexylthio, heptylthio,isoheptylthio, octylthio or isooctylthio.

In general, acyl represents phenyl or straight-chain or branched loweralkyl, having 1 to about 6 carbon atoms, which are bonded via a carbonylgroup. Phenyl, and alkyl radicals having up to 4 carbon atoms arepreferred. Examples which may be mentioned are: benzoyl, acetyl,ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonl andisobutylcarbonyl.

Alkoxycarbonyl may be represented, for example, by the formula ##STR9##In this formula, alkyl represents a straight-chain or branchedhydrocarbon radical having 1 to 12 carbon atoms. Lower alkoxycarbonylhaving 1 to about 6 carbon atoms in the alkyl part is preferred. Analkoxycarbonyl having 1 to 4 carbon atoms in the alkyl part isparticularly preferred. Examples which may be mentioned are thefollowing alkoxycarbonyl radicals: methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl orisobutoxycarbonyl.

Aryloxycarbonyl may be represented, for example, by the formula-COO-aryl. In this formula, aryl represents, in general, an aromaticradical having 6 to 12 carbon atoms. Examples which may be mentionedare: phenoxycarbonyl and naphthyloxycarbonyl.

Aralkoxycarbonyl may be represented, for example, by the formula-COO-aralkyl. In this formula, aralkyl represents, in general, an arylradical, having 7 to 14 carbon atoms, which is bonded via an alkylenechain, aralkyl radicals having 1 to 6 carbon atoms in the aliphatic partand 6 to 12 carbon atoms in the aromatic part being preferred. Exampleswhich may be mentioned as aralkoxycarbonyl radicals are:benzyloxycarbonyl and naphthylmethyloxycarbonyl.

In the context of the abovementioned definition, heteroaryl represents,in general, a 5- to 6-membered aromatic ring, which may contain, asheteroatoms, oxygen, sulphur and/or nitrogen and to which a furtheraromatic ring may be fused. 5- and 6-membered aromatic rings whichcontain one oxygen, one sulphur and/or up to 2 nitrogen atoms and whichare optionally fused to a benzyl group are preferred. The following maybe mentioned as particularly preferred heteroaryl radicals: thienyl,furyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl,isoquinolyl, quinazolyl, quinoxalyl, thiazolyl, benzothiazolyl,isothiazolyl, oxazolyl, benzoxazolyl, isoxazolyl, imidazolyl,benzimidazolyl, pyrazolyl and indolyl.

In general, halogen represents fluorine, chlorine, bromine or iodine,preferably fluorine, chlorine or bromine. Halogen particularlypreferably represents fluorine or chlorine.

Preferred compounds of the general formula (I) are those in which

R¹ represents hydrogen or lower alkyl,

R² represents hydrogen, lower alkyl, lower alkylcarbonyl, or benzoyl,and

R³ represents quinuclidine or a group of the formula --(CH₂)_(a) --R⁴,--CH₂ --CH═CH--(CH₂)_(b) --R⁴, --CH₂ --C.tbd.C--(CH₂)_(b) --R⁴,##STR10## wherein

a denotes a number 1 to 8,

b denotes a number 0, 1, 2 or 3,

c denotes a number 0, 1 or 2,

d denotes a number 2 or 3,

X denotes oxygen or the group NR⁵,

where

R⁵ represents hydrogen, or represents lower alkyl which is optionallysubstituted by hydroxyl or amino, or represents phenyl, benzyl, loweralkoxycarbonyl, lower alkylsulphonyl or carbamoyl, and

R⁴ denotes cyano or a group of the formula --OR⁶, --COOR⁷, --CONR⁸ R⁹,--SO₂ NR⁸ R⁹, --SO_(m) R¹⁰, NR¹¹ R¹², ##STR11## where

c, d and X have the abovementioned meaning,

A represents hydrogen, lower alkylsulphonyl, acetyl, phenylsulphonyl,tolylsulphonyl or lower alkoxycarbonyl,

R⁶ represents hydrogen, lower alkyl, phenyl, benzyl, loweralkylcarbonyl, lower alkoxycarbonyl or tetrahydronaphthalen-1-yl,

R⁷ represents hydrogen, lower alkyl or phenyl,

R⁸ and R⁹ are identical or different and represent hydrogen, lower alkylor phenyl,

R¹⁰ represents lower alkyl, or represents phenyl which may be up todisubstituted, identically or differently, by fluorine, chlorine,bromine, lower alkyl or lower alkoxy, m represents a number 0, 1 or 2,

R¹¹ and are identical or different and represent hydrogen, lower alkyl,phenyl or benzyl, where the phenyl radicals may be substituted byfluorine, chlorine, bromine, lower alkyl, lower alkoxy ortrifluoromethyl, or represent a group of the formula --COR¹³ or --SO₂R¹⁴,

wherein

R¹³ denotes hydrogen, or denotes an NHR¹⁵ group, or denotes lower alkylor lower alkoxy, or denotes phenyl, benzyl, benzyloxy, thienyl, furyl,pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl,thiazolyl, oxazolyl, isoxazolyl or isothiazolyl which are optionallysubstituted by lower alkyl, lower alkoxy, fluorine, chlorine, bromine,trifluoromethyl, dimethylamino or diethylamino,

R⁴ denotes cyclopropyl, cyclopentyl or cyclohexyl, or lower alkyl whichis optionally substituted by cyano, fluorine, chlorine, bromine,trifluoromethyl or lower alkoxycarbonyl, or phenyl, benzyl, thienyl,furyl, pyrimidyl, pyridyl, quinolyl, isoquinolyl, benzothiazolyl,benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl which areoptionally substituted by lower alkyl, lower alkoxy, fluorine, chlorine,bromine, trifluoromethyl, dimethylamino or diethylamino, or denotes anNR⁸ R⁹ group,

where

and have the abovementioned meaning, and

R¹⁵ denotes lower alkyl which is optionally substituted by cyano,fluorine, chlorine or bromine, or denotes phenyl, benzyl, thienyl,furyl, pyridyl, pyrimidyl, quinolyl, isoquinolyl, benzothiazolyl,benzoxazolyl, thiazolyl, oxazolyl, isoxazolyl or isothiazolyl which areoptionally substituted by lower alkyl, lower alkoxy, fluorine, chlorine,bromine, trifluoromethyl, dimethylamino or diethylamino,

or

R¹¹ and R¹², together with the nitrogen atom, form a ring from theseries comprising ##STR12## wherein

n denotes a number 1 or 2,

or in which

R² and R³, together with the nitrogen atom, form a group of the formula##STR13## wherein

c and d having the abovementioned meaning, and

Y denotes oxygen or an NR⁵ or CH(CH₂)_(e) --NHR⁵ group,

where

R⁵ has the abovementioned meaning, and

e represents a number 0, 1 or 2,

but where

R³ does not denote 3-hydroxypropyl when

R¹ represents methyl and R² represents propyl, and

R³ does not denote 2-methylthioethyl when

R¹ represents hydrogen or methyl and R² represents hydrogen, propyl orpropionyl,

and their salts.

Particularly preferred compounds of the general formula (I) are those inwhich

R¹ represents hydrogen or methyl,

R² represents hydrogen, methyl, ethyl, propyl, isopropyl, acetyl orpropionyl, and

R³ represents quinuclidine or a group of the formula --(CH₂)_(a) --R⁴,--CH₂ --CH═CH--(CH₂)_(b) --R⁴, --CH₂ --C.tbd.C--(CH₂)_(b) --R²,##STR14## wherein

a denotes a number 1 to 6,

b denotes a number 0, 1 or 2,

c denotes a number 1 or 2,

d denotes the number 2,

X denotes the NR⁵ group,

where

R⁵ represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, phenyl, benzyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, methylsulphonyl, ethylsulphonyl orcarbamoyl, and

R⁴ denotes cyano or a group of the formula --OR⁶, --COOR⁷, --CONR⁸ R⁹,--SO_(m) R¹⁰, --NR¹¹ R¹², ##STR15## where

c, d and X have the abovementioned meaning,

A represents hydrogen, methylsulphonyl, phenylsulphonyl, tolylsulphonyl,methoxycarbonyl or ethoxycarbonyl,

R⁶ represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl,isobutyl, acetyl, ethylcarbonyl, propylcarbonyl, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl or tetrahydronaphthalen-1-yl,

R⁷ represents hydrogen, methyl, ethyl, propyl, isopropyl, butyl orisobutyl,

R⁸ and R⁹ are identical or different and represent hydrogen, methyl,ethyl, propyl, isopropyl, butyl or isobutyl,

R¹⁰ represents methyl, ethyl, propyl, isopropyl, butyl, isobutyl, orrepresents phenyl which is optionally substituted by fluorine, chlorine,methyl, ethyl, propyl or isopropyl,

m represents a number 0, 1 or 2,

R¹¹ and R¹² are identical or different, and represent hydrogen, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, or represent phenyl which isoptionally substituted by fluorine, chlorine, methyl or methoxy, orrepresent a --COR¹³ or --SO₂ R¹⁴ group,

wherein

R¹³ denotes an NHR¹⁵ group, or denotes methyl, ethyl, propyl, isopropyl,methoxy, ethoxy, propoxy or isopropoxy, or denotes phenyl, benzyl,benzyloxy, thienyl, furyl, pyridyl, pyrimidyl, quinolyl or isoquinolylwhich are optionally substituted by methyl, methoxy, fluorine orchlorine,

R¹⁴ denotes methyl, ethyl, propyl, isopropyl, butyl or isobutyl whichare optionally substituted by fluorine, chlorine, methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl orisobutoxycarbonyl, or denotes phenyl, thienyl, furyl, pyridyl,pyrimidyl, quinolyl or isoquinolyl which are optionally substituted bymethyl, ethyl, propyl, isopropyl, methoxy, fluorine or chlorine, ordenotes an NR⁸ R⁹ group, where

R⁸ and R⁹ have the abovementioned meaning,

and

R¹⁵ denotes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,isopentyl, hexyl or isohexyl which are optionally substituted byfluorine or chlorine, or denotes phenyl which may be substituted byfluorine, chlorine, methyl or methoxy,

or

R¹¹ and R¹², together with the nitrogen atoms, form a ring from theseries comprising ##STR16## wherein

n denotes a number 1 or 2,

or in which

R² and R³, together with the nitrogen atom, form a group of the formula##STR17## wherein

c and d have the abovementioned meaning, and

Y denotes a group of the formula NR⁵ or CH(CH₂)_(e) --NHR⁵

where

R⁵ has the abovementioned meaning and

e represents a number 1 or 2,

but where

R³ does not denote 3-hydroxypropyl when

R¹ represents methyl and R² represents propyl, and

R³ does not denote 2-methylthioethyl when

R¹ represents hydrogen or methyl and R² represents hydrogen, propyl orpropionyl,

and their salts.

Particularly preferred compounds of the general formula (I) are thosewhich contain a basic nitrogen. Basic nitrogen is taken to mean nitrogengroups, for example amino groups, which are not deactivated. A nitrogengroup can be deactivated by electron-attracting groups. Suchdeactivating groups may be acyl or sulphonyl groups which are bonded tothe nitrogen. These preferably include alkyl-, aryl- or aralkylcarbonylgroups, alkyl-, aryl- or aralkylsulphonyl or -sulphamoyl groups,carboxyl, carbamoyl or alkoxy-, aryloxy- or aralkoxycarbonyl groups.

Examples which may be mentioned are the following substituted basic2-aminotetralins:

N-6-Chlorohexyl-N'-{3-[N-(8-methoxy-1,2,3,4-tetrahydro-2-naphthyl)-N-propyl]amino}propylurea

8-Methoxy-2-[N-propyl-N-(3-phthalimidoyl-propyl)]amino-1,2,3,4-tetrahydronaphthalene

2-(2-Ethoxycarbonylamido-ethyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(Diethylcarboxamidoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-{N-[3-(4-Fluorobenzenesulphonamido)propyl]-N-propyl}-amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(3-Aminopropyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

8-Methoxy-2-[N-(2-toluenesulphonamidoethyl)-N-propyl]amino-1,2,3,4-tetrahydronaphthalene

2-{4-[N-(8-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl]amino-butyl}-1,2-benzoisothiazol-3(2H)-one1,1-dioxide

2-[N-(2-Methanesulphonamido-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(2-Aminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-(N-Ethoxycarbonylmethyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-(N-Cyanomethyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

N-{2-[N-(8-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl]amino}ethyl-N'-phenylurea

8-Methoxy-2-[N-propyl-N-(2-nicotinoylamino-ethyl)]amino-1,2,3,4-tetrahydronaphthalene

2-{N-[2-(3-Chloropropylsulphonamido)ethyl]-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2{N-[2-(4-Chlorobutylsulphonamido)ethyl]-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(2-Dimethylaminosulphonylamido)ethyl-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(2-Cyanoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(2-Carboxamido-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(2-Ethyl-carbonyldioxy-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-{2-[-Propyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)]amino}ethyl-perhydrothiazine1,1-dioxide

2-{2-[N-propyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)]amino}ethyl-isothiazolidine1,1-dioxide

2-(4-Methylpiperazin-1-yl)-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-(N-Quinuclidin-3-yl-N-propyl)amino-8-methoxy-1.2,,3,4-tetrahydronaphthalene

2-(N-Diethylcarboxamidomethyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(2-Methoxycarbonylamido-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-(2-Diethylaminoethyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(2-Methylaminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(2-Diethylaminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-(1-Ethoxycarbonyl-piperidin-4-yl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-(4-Ethoxycarbonylaminomethyl)piperidin-1-yl-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-(3-Dimethylaminopropyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(3-Dimethylaminopropyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-(1-Methylpiperidin-4-yl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(3-Dimethylaminopropyl)-N-propionyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

2-[N-(2-Diethylaminoethyl)-N-acetyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

N-6-Chlorohexyl-N'-{3-[N-(8-methoxy-1,2,3,4-tetrahydro-2-naphthyl)-N-propyl]amino}propylureahydrochloride

8-Methoxy-2-[N-propyl-N-(3-phthalimidoyl-propyl)]amino-1,2,3,4-tetrahydronaphthalenehydrochloride

2-(2-Ethoxycarbonylamido-ethyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-[N-(Diethylcarboxamidoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-{N-[3-(4-Fluorobenzenesulphonamido)propyl]-N-propyl}-amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

8-Methoxy-2-[N-(2-toluenesulphonamidoethyl)-N-propyl]amino-1,2,3,4-tetrahydronaphthalenehydrochloride

2-[N-(2-Methanesulphonamido-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-[N-(2-Aminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

2-(N-Cyanomethyl-N-propyl)amino-8-methoxy-1,2,3,4tetrahydronaphthalenehydrochloride

N-{2-[N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl]amino}ethyl-N'-phenylureahydrochloride

8-Methoxy-2-[N-propyl-N-(2-nicotinoylamino-ethyl)]amino-1,2,3,4-tetrahydronaphthalenehydrochloride

2-{N-[2-(3-Chloropropylsulphonamido]-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

2-{N-[2-(4-Chlorobutylsulphonamido)ethyl]-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-[N-(2-Dimethylaminosulphonlamido)ethyl-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-[N-(2-Cyanoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-[N-(2-Carboxamido-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-[N-(2-Ethyl-carbonyldioxy-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-{2-[N-Propyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)]amino}ethyl-perhydrothiazine1,1-dioxide hydrochloride

2-{2-[N-Propyl-N-(8-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)]amino}ethyl-isothiazolidine1,1-dioxide hydrochloride

2-(4-Methylpiperazin-1-yl)-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-(N-Quinuclidin-3-yl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

2-(N-Diethylaminocarboxamidomethyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene dihydrochloride

2-[N-(2-Methoxycarbonylamido-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-(2-Diethylaminoethyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-[N-(2-Methylaminomethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

2-[N-(2-Diethylaminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

2-(1-Carbethoxypiperidin-4-yl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

2-(4-Ethoxycarbonylamido-methyl)piperidin-1-yl-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-(3-Dimethylaminopropyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

2-[N-(3-Dimethylaminopropyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

2-(1-Methylpiperidin-4-yl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

2-[N-(3-Dimethylaminopropyl)-N-propionyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

2-[N-(2-Diethylaminoethyl)-N-acetyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

Furthermore, a process for the preparation of the substituted basic2-aminotetralins according to the invention, of the formula (I)##STR18## in which

R¹ represents hydrogen or alkyl,

R² represents hydrogen, alkyl or acyl, and

R³ represents quinuclidine or a group of the formula --(CH₂)_(a) --R⁴,--CH₂ --CH═CH--(CH₂)_(b) --R⁴, --CH₂ --C.tbd.C--(CH₂)_(b) --R⁴,##STR19## wherein

a denotes a number from 1 to 10,

b denotes a number 0, 1, 2, 3 or 4,

c denotes a number 0, 1 or 2,

d denotes a number 2 or 3,

X denotes oxygen, sulphur or NR⁵,

where

R⁵ represents hydrogen or cycloalkyl, or represents alkyl which may besubstituted by halogen, hydroxyl, amino, alkylamino, dialkylamino,carbamoyl or sulphamoyl, or represents aryl, heteroaryl, aralkyl,alkoxycarbonyl, alkylsulphonyl, phenylsulphonyl, tolylsulphonyl,benzylsulphonyl, formyl, carbamoyl or sulphamoyl, and

R⁴ denotes cyano or a group of the formula --OR⁶, --COOR⁷, --CONR⁸ R⁹,--SO₂ NR⁸ R⁹, --SO_(m) R¹⁰, --NR¹¹ R¹², ##STR20## where

c, d and X have the abovementioned meaning, A represents hydrogen,alkylsulphonyl, phenylsulphonyl, tolylsulphonyl, benzylsulphonyl, acylor alkoxycarbonyl,

R⁶ represents hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,tetrahydronaphthalen-1-yl or benzothiadiazolyl,

R⁷ represents hydrogen, alkyl, alkenyl, aryl or aralkyl,

R⁸ and R⁹ are identical or different and represent hydrogen, alkyl, arylor aralkyl,

R¹⁰ represents alkyl, cycloalkyl, aryl or aralkyl, where the arylradicals may be up to trisubstituted, identically or differently, byhalogen, cyano, alkyl, alkoxy, trifluoromethyl or trifluoromethoxy,

m represents a number 0, 1 or 2,

R¹¹ and R¹² are identical or different and represent hydrogen, alkyl,aryl or aralkyl, where the aryl radicals may be substituted by halogen,cyano, alkyl, alkoxy or trifluoromethyl, or

represent a group of the formula --COR¹³ or --SO₂ R¹⁴,

wherein

R¹³ denotes hydrogen, or denotes an NHR¹⁵ group, or denotes alkyl oralkoxy, or denotes aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, wherethe radicals mentioned may be up to trisubstituted, identically ordifferently, by alkyl, alkoxy, alkylthio, halogen, cyano,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino,alkylamino or dialkylamino,

R¹⁴ denotes cycloalkyl, or denotes alkyl which may be substituted bycyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, ordenotes aryl, aralkyl or heteroaryl, where the radicals mentioned may beup to trisubstituted, identically or differently, by alkyl, alkoxy,alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, amino, alkylamino or dialkylamino or denotes an NR⁸R⁹ group,

where

R⁸ and have the abovementioned meaning and

R¹⁵ denotes hydrogen, or denotes cycloalkyl, or denotes alkyl which isoptionally substituted by cyano, halogen, trifluoromethyl ortrifluoromethoxy, or denotes aryl, aralkyl or heteroaryl where the arylradicals may be up to trisubstituted, identically or differently, byalkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, amino, alkylamino ordialkylamino,

or where

R¹¹ and R¹², together with the nitrogen atom, form a ring from theseries comprising ##STR21## wherein

n denotes a number 1 or 2,

or in which

R² and R³, together with the nitrogen atom, form a group of the formula##STR22## wherein

c and d have the abovementioned meaning, and

Y denotes oxygen, sulphur or a group of the formula NR⁵ or CH(CH₂)_(e)--NHR⁵,

where

R⁵ has the abovementioned meaning, and

e represents a number 0 to 4,

but where

R³ does not denote 3-hydroxypropyl when

R¹ represents methyl and R² represents propyl,

and where

R³ does not denote 2-methylthioethyl when

R¹ represents hydrogen or methyl and R² represents hydrogen, propyl orpropionyl,

and their salts, has been found, which is characterized in thattetralones of the general formula (II) ##STR23## in which

R¹ has the meaning mentioned, are reacted with amines of the generalformula (III) ##STR24## in which

R² and R³ have the meaning mentioned, but R² may not represent acyl, ininert solvents, if appropriate in the presence of auxiliaries, theintermediates are then reduced in inert solvents, then, in the case ofthe preparation of the acyl compounds (R² =acyl), reacted with anacylating agent, then, if appropriate, functional groups are convertedinto other functional groups by reduction, hydrolysis, oxidation orreaction with electrophilic reagents and then, in the case of thepreparation of the salts, reacted with the appropriate acid.

The process according to the invention may be described, for the case ofthe reaction with cyclic amines, by equation (a) and, for the case ofthe reaction with open-chain amines, by equation (b): ##STR25##

The tetralones, of the general formula (II), used as starting materialsare known or can be prepared by known methods [P.A. Robins, J. Walker,J. Chem. Soc. 1958, 409; Cornforth et al. J. Chem. Soc. 1942, 689].

The amines, of the general formula (III), used as starting compounds areknown or can be prepared by known methods [Houben-Weyl's "Methoden derorganischen Chemie" (Methods of Organic Chemistry) vol. XI/1 and XI/2].

In the case of the reaction with primary amines the intermediates areSchiff bases, and in the case of the reaction with secondary amines theintermediates are enamines or immonium salts.

The intermediates are prepared by reaction of the tetralones (II) withamines (III) in inert organic solvents, if appropriate in the presenceof a catalyst and if appropriate in the presence of a dehydrating agent.

The process according to the invention can be carried out in two steps,i.e. with isolation of the intermediates. It is also possible to carryout the process according to the invention as a one-pot process.

Suitable inert solvents here are those conventional organic solventswhich do not change under the reaction conditions. These preferablyinclude alcohols such as methanol, ethanol, propanol or isopropanol, orethers such as diethyl ether, butyl methyl ether, dioxane,tetrahydrofuran, glycol dimethyl ether or diethylene glycol dimethylether, or halogenated hydrocarbons such as, for example, methylenechloride, chloroform or carbon tetrachloride, or hydrocarbons such asbenzene, toluene, xylene, or petroleum fractions, or amides such asdimethylformamide or hexamethylphosphoric triamide, or acetic acid.

In addition, it is possible to use mixtures of the solvents mentioned.

In general, protonic acids are used as catalysts. These preferablyinclude inorganic acids such as, for example, hydrochloric acid orsulphuric acid, or organic carboxylic acids having 1-6 C atoms,optionally substituted by fluorine, chlorine and/or bromine, such as,for example, acetic acid, trifluoroacetic acid, trichloroacetic acid orpropionic acid, or sulphonic acids having C₁ -C₄ alkyl radicals orhaving aryl radicals, such as, for example, methanesulphonic acid,ethanesulphonic acid, benzenesulphonic acid or toluenesulphonic acid.

The water formed during the reaction may be removed, if appropriate, asa mixture with the solvent used during or after the reaction, forexample by distillation or by addition of dehydrating agents, such as,for example, phosphorus pentoxide or, preferably, by molecular sieve.

The reaction is generally carried out in a temperature range from 0° C.to +150° C., preferably from +20° C. to +100° C.

In the case of removal of the water formed during the reaction byazeotropic distillation with the solvents used, the reaction ispreferably carried out at the boiling temperature of the azeotrope.

The reaction can be carried out at atmospheric, increased or reducedpressure (e.g. 0.5-5 bar). In general, the reaction is carried out atatmospheric pressure.

When carrying out the reaction, the starting compounds are generallyemployed in a tetralone (II) to amine (III) molar ratio of 0.5 : 2 to 1: 2. Molar amounts of the reactants are used preferably.

The intermediates are reduced either by hydrogen in water or inertorganic solvents such as alcohols, ethers or halogenated hydrocarbons,or mixtures thereof, using catalysts such as Raney nickel, palladium,palladium on animal charcoal, or platinum, or using hydrides in inertsolvents, if appropriate in the presence of a catalyst.

The reaction is preferably carried out using hydrides, such as complexborohydrides or aluminium hydrides. Sodium borohydride, lithium aluminumhydride or sodium cyanoborohydride are particularly preferably employedhere.

Suitable solvents here are all inert organic solvents which do notchange under the reaction conditions. These preferably include alcoholssuch as methanol, ethanol, propanol or isopropanol, or ethers such asdiethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether ordiethylene glycol dimethyl ether, or amides such as hexamethylphosphorictriamide, or dimethylformamide, or acetic acid. It is also possible touse mixtures of the solvents mentioned.

In general, protonic acids are used as catalysts during the reduction.These preferably include inorganic acids such as, for example,hydrochloric acid or sulphuric acid, or organic carboxylic acids having1-6 C atoms, optionally substituted by fluorine, chlorine and/orbromine, such as, for example, acetic acid, trifluoroacetic acid,trichloroacetic acid or propionic acid, or sulphonic acids having C₁ -C₄-alkyl radicals or having aryl radicals, such as, for example,methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid ortoluenesulphonic acid.

When carrying out the process according to the invention, it has provenfavorable to carry out the reaction of the tetralones (II) with theamines (III) in an inert solvent, preferably in ethyl acetate or inalcohols such as, for example, methanol, ethanol, propanol orisopropanol, or mixtures thereof, in the presence of inorganic ororganic acids, such as, for example, hydrochloric acid or acetic acid,and in the presence of a reducing agent, preferably complex hydridessuch as, for example, sodium borohydride or sodium cyanoborohydride, ifappropriate in the presence of a dehydrating agent, preferably molecularsieve, as a one-pot process.

In this case, the reaction is carried out in a temperature range from 0°C. to +150° C., preferably from 0° C. to +100° C., at atmosphericpressure. It is also possible to carry out the reaction at a reducedpressure or at an increased pressure (e.g. in a Carius tube).

If the process according to the invention is carried out as a one-potreaction, it has proved favorable to employ the amine in an excess of upto 10-fold, preferably up to 5-fold, to the tetralone.

In general, the acylation is carried out in inert solvents by reactionof the compounds according to the invention, having R² =H, withacylating agents, preferably reactive carboxylic acid derivatives, ifappropriate in the presence of bases.

Inert solvents here are, in general, water or organic solvents which donot change under the reaction conditions. These preferably includealcohols such as methanol, ethanol, propanol or isopropanol, or etherssuch as diethyl ether, tetrahydrofuran, dioxane or glycol dimethylether, or hydrocarbons such as benzene, toluene, xylene or petroleumfractions, or halogenated hydrocarbons such as methylene chloride,chloroform or carbon tetrachloride, or carboxylic acids such as aceticacid or propionic acid, or carboxylic acid anhydrides such as propionicanhydride or acetic anhydride. It is also possible to employ mixtures ofthe solvents mentioned.

Reactive carboxylic acid derivatives are, in general, carboxylic acidhalides or carboxylic acid anhydrides. Aliphatic carboxylic acidbromides, chlorides or anhydrides are preferred here. Acetyl chloride,acetyl bromide, acetic anhydride, propionyl chloride, propionyl bromideand propionic anhydride are particularly preferred.

Conventional basic compounds can be employed as bases for basicreactions. These preferably include allaki metal or alkaline earth metalhydroxides or carbonates, such as, for example, lithium hydroxide,sodium hydroxide, potassium hydroxide or barium hydroxide, sodiumcarbonate or potassium carbonate, or alkali metal alcoholates such as,for example, sodium methanolate, sodium ethanolate, potassiummethanolate or potassium ethanolate.

In general, the acylation is carried out in a temperature range from-20° C. to +100° C., preferably from 0° C. to +50° C., at atmosphericpressure.

In the context of the present invention, the disubstituted2-aminotetralins (Ia) correspond to the general formula ##STR26## inwhich

R¹ and R³ have the meaning mentioned and

R^(2') represents alkyl.

In the context of the present invention, the alkyl-substituted2-aminotetralins (Ib) correspond to the general formula ##STR27## inwhich

R¹ has the abovementioned meaning and

R^(2') represents alkyl.

In the context of the present invention, the monosubstituted basic2-aminotetralins (Ic) correspond to the formula ##STR28## in which

R¹ and R³ have the meaning mentioned.

A further process for the preparation of the compounds of the generalformula (Ia) has been found, starting from the compounds of the formulae(Ib) and (Ic) according to the invention, in which process the startingcompounds (Ib) and (Ic) are obtained by the abovementioned process,according to the invention, of reductive amination. The compounds of thegeneral formula (Ia) ##STR29## in which

R¹ represents hydrogen or alkyl,

R^(2') represents alkyl,

R³ represents quinuclidine or a group of the formula --(CH₂)_(a) --R⁴,--CH₂ --CH═CH--(CH₂)_(b) --R⁴, --CH₂ --C.tbd.C--(CH₂)_(b) --R⁴,##STR30## wherein

a denotes a number from 1 to 10,

b denotes a number 0, 1, 2, 3 or 4,

c denotes a number 0, 1 or 2,

d denotes a number 2 or 3,

X denotes oxygen, sulphur or NR⁵,

where

R⁵ represents hydrogen or cycloalkyl, or represents alkyl which may besubstituted by halogen, hydroxyl, amino, alkylamino, dialkylamino,carbamoyl or sulphamoyl or, represents aryl, heteroaryl, aralkyl,alkoxycarbonyl, alkylsulphonyl, phenylsulphonyl, tolylsulphonyl,benzylsulphonyl, formyl, carbamoyl or sulphamoyl,

and

R⁴ denotes cyano or a group of the formula --OR⁶, --COOR⁷, --CONR⁸ R⁹,--SO₂ NR⁸ R⁹, --SO_(m) R¹⁰, --NR¹¹ R¹², ##STR31## where

c, d and X have the abovementioned meaning,

A represents hydrogen, alkylsulphonyl, phenylsulphonyl, tolylsulphonyl,benzylsulphonyl, acyl or alkoxycarbonyl,

R⁶ represents hydrogen, alkyl, alkenyl, cycloalkyl, aryl, aralkyl, acyl,alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl,tetrahydronaphthalen-1-yl or benzothiadiazolyl,

R⁷ represents hydrogen, alkyl, alkenyl, aryl or aralkyl,

R⁸ and R⁹ are identical or different and represent hydrogen, alkyl, arylor aralkyl,

R¹⁰ represents alkyl, cycloalkyl, aryl or aralkyl, where the arylradicals may be up to trisubstituted, identically or differently, byhalogen, cyano, alkyl, alkoxy, trifluoromethyl or trifluoromethoxy,

m represents a number 0, 1 or 2,

R¹¹ and Rn12 are identical or different and represent hydrogen, alkyl,aryl or aralkyl, where the aryl radicals may be substituted by halogen,cyano, alkyl, alkoxy or trifluoromethyl, or

represent a group of the formula --COR¹³ or --SO₂ R¹⁴,

wherein

R¹³ denotes hydrogen, or denotes an NHR¹⁵ group, or denotes alkyl oralkoxy, or denotes aryl, aryloxy, aralkyl, aralkoxy or heteroaryl, wherethe radicals mentioned may be up to trisubstituted, identically Drdifferently, by alkyl, alkoxy, alkylthio, halogen, cyano,trifluoromethyl, trifluoromethoxy, trifluoromethylthio, amino,alkylamino or dialkylamino,

R¹⁴ denotes cycloalkyl, or denotes alkyl which may be substituted bycyano, halogen, trifluoromethyl, trifluoromethoxy or alkoxycarbonyl, ordenotes aryl, aralkyl or heteroaryl, where the radicals mentioned may beup to trisubstituted, identically or differently, by alkyl, alkoxy,alkylthio, halogen, cyano, trifluoromethyl, trifluoromethoxy,trifluoromethylthio, amino, alkylamino or dialkylamino or

denotes an NR⁸ R⁹ group,

where

R⁸ and R⁹ have the abovementioned meaning and

R¹⁵ denotes hydrogen, or denotes cycloalkyl, or denotes alkyl which isoptionally substituted by cyano, halogen, trifluoromethyl ortrifluoromethoxy, or denotes aryl, aralkyl or heteroaryl where the arylradicals may be up to trisubstituted, identically or differently, byalkyl, alkoxy, alkylthio, halogen, cyano, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, amino, alkylamino ordialkylamino,

or where

R¹¹ and R¹², together with the nitrogen atom, form a ring from theseries comprising ##STR32## wherein

n denotes a number 1 or 2,

or in which

R² and R³, together with the nitrogen atom, form a group of the formula##STR33## wherein

c and d have the abovementioned meaning, and

Y denotes oxygen, sulphur or a group of the formula NR⁵ or CH(CH₂)_(e)--NHR⁵, where

R⁵ has the abovementioned meaning, and

e represents a number 0 to 4,

but where

R³ does not denote 3-hydroxypropyl when

R¹ represents methyl and R² represents propyl,

and where

R³ does not denote 2-methylthioethyl when

R¹ represents hydrogen or methyl and R² represents propyl,

and their salts can be prepared by

[A] reacting alkyl-substituted 2-aminotetralins of the general formula(Ib) ##STR34## in which

R¹ and R^(2') have the abovementioned meaning, with halogen compounds ofthe general formula (IV)

    Hal--R.sup.3                                               (IV)

in which

R³ has the abovementioned meaning and

Hal represents halogen, preferably chlorine, bromine or iodine,

in inert solvents, in the presence of bases, if appropriate in thepresence of reaction accelerators,

then converting, if appropriate, functional groups into other functionalgroups by reduction, hydrolysis, oxidation or reaction withelectrophilic reagents,

and then, in the case of the preparation of the salts, reacting withappropriate acids,

or by

[B] reacting monosubstituted basic 2-aminotetralins of the generalformula (Ic) ##STR35## in which

R¹ and R³ have the abovementioned meaning, with compounds of the generalformula (V)

    D--R.sup.2'                                                (V)

in which

R^(2') has the abovementioned meaning and

D represents a carbonyl oxygen, in inert solvents, if appropriate in thepresence of a catalyst,

then reducing the intermediates obtained in inert solvents,

then converting, if appropriate, functional groups into other functionalgroups by reduction, hydrolysis, oxidation or reaction withelectrophilic reagents,

and then, in the case of the preparation of the salts, reacting withappropriate acids.

Depending on the type of the starting compounds used, both processversions A and B can be described by the following equations: ##STR36##

Process version A

Those conventional organic solvents which do not change under thereaction conditions can be used here as solvents. These preferablyinclude alcohols such as methanol, ethanol, propanol or isopropanol, orethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethylether or butyl methyl ether, or ketones such as acetone or butanone, oramides such as dimethylformamide or hexamethylphosphoric triamide, ordimethyl sulphoxide, acetonitrile or ethyl acetate, or halogenatedhydrocarbons such as methylene chloride, chloroform or carbontetrachloride, or pyridine, picoline or N-methylpiperidine. Mixtures ofthe solvents mentioned can likewise be used.

Suitable bases are the conventional inorganic or organic bases. Thesepreferably include alkali metal hydroxides such as, for example, sodiumor potassium hydroxide, or alkali metal carbonates such as sodium orpotassium carbonate, or alkali metal alcoholates such as, for example,sodium or potassium methanolate, or sodium or potassium ethanolate, ororganic amines such as triethylamine, picoline or N-methylpiperidine, oramides such as sodium amide or lithium diisopropylamide, ororganometallic compounds such as butyllithium or phenyllithium.

In general, the reaction is carried out in a temperature range from 0°C. to +150° C., preferably from room temperature to +80° C.

In general, the reaction is carried out at atmospheric pressure.However, it is also possible to carry out the reaction at increased orreduced pressure.

As reaction accelerators, alkali metal iodides, preferably sodium iodideor potassium iodide, are employed in general.

In this reaction, the base is employed in an amount from 1 to 5,preferably from 1 to 2, mols, relative to 1 mol of the halogen compound.The halogen compound is preferably employed in an excess amount of up to10-fold, preferably in an excess amount of up to 5-fold, to thealkyl-substituted 2-aminotetralin (Ib).

Process version B

In the case of the reaction with primary amines the intermediates areSchiff bases, and in the case of the reaction with secondary amines theintermediates are enamines or immonium salts.

The intermediates in the first step are prepared in inert organicsolvents, if appropriate in the presence of a catalyst and ifappropriate in the presence of a dehydrating agent.

The process according to the invention may be carried out in 2 steps,i.e. with isolation of the intermediates. It is also possible to carryout the reduction as a one-pot process.

Suitable inert solvents in this reaction are those conventional organicsolvents which do not change under the reaction conditions. Thesepreferably include alcohols such as methanol, ethanol, propanol orisopropanol, or ethers such as diethyl ether, butyl methyl ether,dioxane, tetrahydrofuran, glycol dimethyl ether or diethylene glycoldiethyl ether, or halogenated hydrocarbons such as, for example,methylene chloride, chloroform or carbon tetrachloride, or hydrocarbonssuch as benzene, toluene, xylene, or petroleum fractions, or amides suchas dimethylformamide or hexamethylphosphoric triamide, or acetic acid.In addition, it is possible to use mixtures of the solvents mentioned.

In general, protonic acids are used as catalysts. These preferablyinclude inorganic acids such as, for example, hydrochloric acid orsulphuric acid, or organic carboxylic acids having 1-6 C atoms,optionally substituted by fluorine, chlorine and/or bromine, such as,for example, acetic acid, trifluoroacetic acid, trichloroacetic acid orpropionic acid, or sulphonic acids having C₁ -C₄ alkyl radicals orhaving aryl radicals, such as, for example, methanesulphonic acid,ethanesulphonic acid, benzenesulphonic acid or toluenesulphonic acid.

The water formed during the reaction may be removed, if appropriate, asa mixture with the solvent used, during or after the reaction, forexample by distillation or by addition of dehydrating agents, such as,for example, phosphorus pentoxide, or preferably by molecular sieve.

In general, the reaction is carried out in a temperature range from 0°C. to +150° C., preferably from +20° C. to +100° C.

In the case of removal of the water formed during the reaction byazeotropic distillation with the solvents used, the reaction ispreferably carried out at the boiling temperature of the azeotrope.

The reaction can be carried out at atmospheric, increased and at reducedpressure (e.g. 0.5-5 bar). In general, the reaction is carried out atatmospheric pressure.

When carrying out the reaction, the compound (V) is employed in anamount from 0.1-10, preferably from 0.5-5 mols relative to 1 mol ofmonosubstituted basic 2-aminotetralin (Ic).

The intermediates are reduced either by hydrogen in water or in inertorganic solvents such as alcohols, ethers or halogenated hydrocarbons,or mixtures thereof, using catalysts such as Raney nickel, palladium,palladium on animal charcoal, or platinum, or using hydrides in inertsolvents, if appropriate in the presence of a catalyst.

The reaction is preferably carried out using hydrides, such as complexborohydrides or aluminium hydrides. Sodium borohydride, lithium aluminumhydride or sodium cyanoborohydride are particularly preferably employedhere.

Suitable solvents in this reaction are all inert organic solvents whichdo not change under the reaction conditions. These preferably includealcohols such as methanol, ethanol, propanol or isopropanol, or etherssuch as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl etheror diethylene glycol dimethyl ether or amides such ashexamethylphosphoric triamide or dimethylformamide, or acetic acid. Itis also possible to use mixtures of the solvents mentioned.

In general, protonic acids are used as catalysts during the reduction.These preferably include inorganic acids such as, for example,hydrochloric acid or sulphuric acid, or organic carboxylic acids having1-6 C atoms, optionally substituted by fluorine, chlorine and/orbromine, such as, for example, acetic acid, trifluoroacetic acid,trichloroacetic acid or propionic acid, or sulphonic acids having C₁ -C₄-alkyl radicals or having aryl radicals, such as, for example,methanesulphonic acid, ethanesulphonic acid, benzenesulphonic acid ortoluenesulphonic acid.

When carrying out the process according to the invention, it has provedfavorable to carry out the reaction of the compounds (V) with the amines(Ic) in an inert solvent, preferably in acetic acid or alcohols such as,for example, methanol, ethanol, propanol or isopropanol, or mixturesthereof, in the presence of inorganic or organic acids, such as, forexample, hydrochloric acid or acetic acid, and in the presence of areducing agent, preferably complex hydrides such as, for example, sodiumborohydride or sodium cyanoborohydride, if appropriate in the presenceof a dehydrating agent, preferably molecular sieve, as a one-potprocess.

In this case, the reaction is carried out in a temperature range from 0°C. to +150° C., preferably from 0° C. to +100° C., at atmosphericpressure. It is also possible to carry out the reaction at reducedpressure or at increased pressure (e.g. in a Carius tube).

If the process according to the invention is carried out as a one-potreaction, it has proved favourable to employ the aminotetralin (Ic) inan amount from 0.1 to 10, preferably 0.5 to 5 mols, relative to 1 mol ofthe compound (V).

The conversion of functional groups into other functional groups in thepreparation process described above is carried out, depending on thetype of the functional groups, by oxidation, reduction, hydrolysis or byreaction with electrophilic reagents and will be described below.

1. In general, the nitrile group is reduced to the amino group usingmetal hydrides, preferably using lithium aluminum hydride, aluminumhydride (prepared, for example, by reaction of lithium aluminum hydridewith 100% strength sulphuric acid or with aluminum chloride), ormixtures thereof, in inert solvents such as ethers or chlorinatedhydrocarbons, preferably ethers such as, for example, tetrahydrofuran,diethyl ether or dioxane, in a temperature range from -20° C. to +100°C., preferably from 0° C. to +50° C., at atmospheric pressure.

In addition, the reduction is possible by hydrogenation of the nitrilesin inert solvents such as alcohols, for example methanol, ethanol,propanol or isopropanol, in the presence of a noble metal catalyst suchas platinum, palladium, palladium on animal charcoal, or Raney nickel,in a temperature range from 0° C. to +150° C., preferably from roomtemperature to +100° C., at atmospheric pressure or at increasedpressure.

The reaction may be illustrated by the following equation: ##STR37##

2. In general, carbamates are converted to N-methylamines by reductionusing hydrides, preferably using lithium aluminum hydride, in inertsolvents such as ethers, hydrocarbons or chlorinated hydrocarbons,preferably in ethers, such as, for example, diethyl ether,tetrahydrofuran or dioxane, in a temperature range from 0° C. to +150°C., preferably from +20° C. to +100° C., at atmospheric pressure.

The reaction may be illustrated by the following equation: ##STR38##

3. -n eneral, alkoxycarbonyl groups are reduced to alcohol groups usinghydrides, preferably using lithium aluminum hydride in inert solventssuch as ethers, hydrocarbons or halogenated hydrocarbons, or mixturesthereof, preferably in ethers, such as, for example, diethyl ether,tetrahydrofuran or dioxane, in a temperature range from 0° C. to +150°C., preferably from +20° C. to +100° C., at atmospheric pressure.

The reaction may be illustrated by the following equation ##STR39##

4. In general, the nitrile group is hydrolyzed to the carboxamide groupusing strong mineral acids, preferably using hydrochloric acid, in inertsolvents such as water and/or alcohols, such as, for example, methanol,ethanol, propanol or isopropanol, in a temperature range from 0° C. to+150° C., preferably from +20° C. to +100° C., at atmospheric pressure.

The reaction may be described by the following equation: ##STR40##

5. A large number of further compounds according to the invention areobtained by reacting NH- or OH-acidic compounds (R⁴ =OH or NR⁵ R⁶, whereR⁵ =H and R⁶ =H, alkyl, aryl or aralkyl) with electrophilic reagents:

a) In general, amines are converted to carboxamides by reaction withcarboxylates in inert solvents such as ethers or their mixtures, orhydrocarbons, preferably in ethers, such as, for example, diethyl ether,tetrahydrofuran or dioxane, if appropriate in the presence of bases suchas alkali metals, alkali metal hydrides, alkali metal alcoholates ororganolithium compounds, preferably in the presence of alkali metalssuch as, for example, sodium, or alkali metal hydrides such as sodiumhydride or potassium hydride, in a temperature range from +20° C. to+150° C., preferably at the boiling temperature of the solvent used, atatmospheric pressure.

In addition, it is possible to prepare the amides using carboxylic acidhalides or anhydrides, preferably using carboxylic acid chlorides, ininert solvents such as ethers, hydrocarbons or halogenated hydrocarbons,or mixtures thereof, preferably in ethers, such as, for example, diethylether or tetrahydrofuran, or halogenated hydrocarbons such as methylenechloride or chloroform, if appropriate in the presence of bases such asalkali metal carbonates, for example sodium carbonate or potassiumcarbonate, or organic amines such as, for example, triethylamine orpyridine, in a temperature range from -20° C. to +100° C., preferablyfrom 0° C. to +60° C., at atmospheric pressure.

The reaction may be illustrated by the following equation: ##STR41##

b) In general, amines are converted to carbamates using carbonic acidderivatives, such as carbonates or carbonyl halides, preferably usingasymmetrical carbonates, particularly preferably using carbonates whichcarry one phenyl ester radical, or using carbonyl chlorides, in inertsolvents such as ethers, hydrocarbons or halogenated hydrocarbons, ormixtures thereof, preferably in ethers such as, for example, diethylether, tetrahydrofuran or dioxane, in a temperature range from 30° C. to+150° C., preferably from 30° C. to +100° C., at atmospheric pressure.

The reaction may be described by the following equation: ##STR42##

c) In general, amines are converted to ureas by reaction withisocyanates in inert solvents such as ethers, hydrocarbons orhalogenated hydrocarbons or mixtures thereof, preferably in ethers suchas, for example, diethyl ether or tetrahydrofuran, or in halogenatedhydrocarbons such as, for example, methylene chloride or chloroform, ina temperature range from -20° C. to +150° C., preferably from 0° C. to+100° C., at atmospheric pressure.

The reaction may be described by the following equation: ##STR43##

d) In general, amides are converted to sulphonamides or aminosulphamoylderivatives using sulphonyl halides or using amidosulphonyl halides,preferably using the corresponding chlorides, in inert solvents such asethers, hydrocarbons or halogenated hydrocarbons, or mixtures thereof,preferably in halogenated hydrocarbons such as, for example, methylenechloride or chloroform, if appropriate in the presence of bases such asalkali metal hydroxides, alkali metal carbonates, alkali metalalcoholates or organic amines, preferably using alkali metal hydroxidessuch as sodium hydroxide or potassium hydroxide, alkali metal carbonatessuch as, for example, sodium carbonate or potassium carbonate, ororganic amines such as triethylamine or pyridine, in a temperature rangefrom -20° C. to +100° C., preferably from 0° C. to +50° C., atatmospheric pressure

The reaction may be illustrated by the following equation: ##STR44##

e) In general, the hydroxyl group is converted to a carbonate byreaction with halogenoformates, preferably with chloroformates, in inertsolvents such as ethers, hydrocarbons or halogenated hydrocarbons,preferably in halogenated hydrocarbons such as methylene chloride orchloroform, or in ethers such as diethyl ether or tetrahydrofuran, ifappropriate in the presence of bases such as alkali metal hydroxides,alkali metal carbonates or organic amines, preferably in the presence oforganic amines such as triethylamine, pyridine, picoline ordimethylaminopyridine, in a temperature range from -20° C. to 100° C.,preferably from 0° C. to +30° C., at atmospheric pressure.

The reaction may be illustrated by the following equation: ##STR45##

f) In general, cyclic sulphonamides are prepared by reaction ofintramolecular electrophiles in inert dipolar aproptic solvents,preferably in dimethylformamide, hexamethylphosphoric triamide ordimethyl sulphoxide, if appropriate in the presence of bases such asalkali metals, alkali metal hydrides, alkali metal amides, alkali metalalcoholates or organolithium compounds, preferably in the presence ofalkali metal hydrides such as sodium hydride or potassium hydride, oralkali metal amides such as sodium amide or lithium diisopropylamide, ifappropriate in the presence of catalytic amounts of an alkali metaliodide, for example sodium iodide or potassium iodide, in a temperaturerange from -20° C. to +100° C., preferably from 0° C. to +50° C., atatmospheric pressure.

The reaction may be illustrated by the following equation: ##STR46##

5. In general the thioether group is oxidized to sulphoxides orsulphones using oxidants such as peroxo compounds or hydrogen peroxideitself, preferably using hydrogen peroxide, in inert solvents such ascarboxylic acids and carboxylic acid anhydrides, preferably in aceticacid, in a temperature range from -20° C. to +100° C., preferably from0° C. to +50° C. The reaction may be illustrated by the followingequation: ##STR47##

In addition to varying the functional groups in R³,8-hydroxy-substituted 2-aminotetralins (R¹ =H) are accessible from thecorresponding 8-methoxy-substituted compounds (R¹ =CH₃) by knowndealkylation methods [T. Green, Protective Groups in Organic Chemistry,page 89, 1st edition, J. Wiley & Sons, New York, 1981]. Expediently,those methods are used in each case which are compatible with the natureof the radical R⁴.

In addition, it is possible to prepare disubstituted 2-aminotetralins(Ia) in which R¹ and R² have the abovementioned meaning and R³represents a 2-cyanoethyl group, by reacting alkyl-substituted2-aminotetralins (Ib) with acrylonitrile, if appropriate in the presenceof a catalyst, in particular copper acetate.

In addition, it is possible to introduce the radical R³ by a Mannichreaction (by reacting alkyl-substituted 2-aminotetralins (Ib) withformaldehyde and CH-acidic compounds, in particular having acetylenegroups).

The following may be used according to the invention, for example, astetralones: 8-Hydroxytetralone and 8-methoxytetralone.

The amines of the general formula (III) employed as starting compoundsare known or can be prepared by known methods [Houben-Weyl's "Methodender organischen Chemie" (Methods of Organic Chemistry), vol. XI/1 andXI/2].

The following may be used according to the invention, for example, asamines: methylamine, ethylamine, propylamine, isopropylamine,butylamine, 4-dimethylaminobutylamine, 4-diethylaminobutylamine,3-dimethylaminopropylamine, 3-diethylaminopropylamine,2-dimethylaminoethylamine, 2-diethylaminoethylamine,2-amino-1-ethoxycarbonylamido-ethane,3-amino-1-ethoxycarbonylamido-propane,4-amino-1-ethoxycarbonylamido-butane, 3-aminoquinuclidine,2-[(phenylaminocarbonyl)amino]ethylamine,2-[(phenylaminocarbonyl)amino]propylamine, 4-aminomethylpiperidine,4-(ethoxycarbonyl)amino-ethyl-piperidine, N-methylpiperazine,4-amino-1-carboxy-ethyl-piperidine, N,N-dimethylpropylidene-diamine,N,N-diethylpropylidene-diamine, N,N-diethylethylidene-diamine,N,N-dimethylethylene-diamine, N-(2-aminoethyl)ethylcarbamate andN-(2-aminoethyl)propylcarbamate.

The halogen compounds of the general formula (IV) are known or can beprepared by known methods [Beilstein's Handbuch der organischen Chemie(Beilstein's Handbook of Organic Chemistry) 2, 197, 201, 250, 278; 3, 9,10; 21, 461, 462, 463].

The following may be used according to the invention, for example, ashalogen compounds: chloroacetonitrile, 2-chloropropionitrile,3-chlorobutyronitrile, 3-bromopropylphthalimide,3-chloropropylphthalimide, 2-bromoethylphthalimide,2-bromoethylphthalimide, 4-bromobutylphthalimide,4-chlorobutylphthalimide, chloroacetic diethylamide, chloroaceticdimethylamide, methyl chloroacetate, ethyl chloroacetate, ethylbromoacetate, methyl bromoacetate,2-γ-bromobutyl-1,2-benzoisothiazol-3(2H)-one 1,1-dioxide and2-γ-bromopropyl-1,2-benzoiso-thiazol-3(2H)-one 1,1-dioxide.

The carbonyl compounds of the general formula (V) employed as startingcompounds are known or can be prepared by known methods [Beilstein'sHandbuch der organischen Chemie (Beilstein's Handbook of OrganicChemistry) 1 594, 629, 662].

The following may be used according to the invention, for example, asketone compounds: acetaldehyde, propionaldehyde and butyraldehyde;

The substances of the general formula (I) according to the inventionhave a high affinity for cerebral 5-hydroxytryptamine receptors of the5-HT₁ type. This affinity of the compounds according to the invention isincreased compared to those known from the prior art (EP-A1-41 488).Agonistic, partially agonistic or antagonistic actions on the serotoninreceptor are connected with this, against which the known substanceshave purely agonistic properties.

The high-affinity ligands, described in the present invention, for theserotonin-1 receptor thus represent better active compounds forcombating diseases which are characterized by disturbances to theserotoninergic system, particularly when involving receptors which havea high affinity to 5-hydroxytryptamine (5-HT₁ type). They are thereforesuitable for the treatment of diseases of the central nervous system,such as anxiety, tension and depression, sexual dysfunctions caused bythe central nervous system, and insomnia. The substances according tothe invention are furthermore suitable for treatment of cognitivedeficits, as arise, for example, in senile dementia and in Alzheimer'sdisease, and other brain-function disturbances. In addition, theseactive compounds are also suitable for modulation of the cardiovascularsystem. They also engage in the regulation of the cerebral blood supply,and thus represent effective agents for combating migraine. Thecompounds according to the invention can likewise be employed forcombating pain. They are also suitable for combating diseases of theintestinal tract, which are characterized by disturbances of theserotoninergic system.

The new active compounds can be converted in a known manner into thecustomary formulations, such as tablets, dragees, pills, granules,aerosols, syrups, emulsions, suspensions and solutions, using inertnon-toxic, pharmaceutically suitable excipients or solvents. Thetherapeutically active compound should in each case be present here in aconcentration of about 0.5 to 90% by weight of the total mixture, thatis to say in amounts which suffice to achieve the dosage rangeindicated.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or excipients, optionally with the use ofemulsifiers and/or dispersing agents, and, for example, when using wateras a diluent, organic solvents can optionally be used as auxiliarysolvents.

Examples of auxiliary substances which may be mentioned are: water,non-toxic organic solvents, such as paraffins (for example petroleumfractions), vegetable oils (for example groundnut oil/sesame oil),alcohols (for example ethyl alcohol and glycerol), excipients, such as,for example, ground natural minerals (for example kaolins, aluminas,talc and chalk), ground synthetic minerals (for example highly dispersesilica and silicates) and sugars (for example sucrose, lactose andglucose), emulsifiers (for example polyoxyethylene fatty acid esters,polyoxyethylene fatty alcohol ethers, alkylsulphonates andarylsulphonates), dispersants (for example lignin, sulphite wasteliquors, methylcellulose, starch and polyvinylpyrrolidone) andlubricants (for example magnesium stearate, talc, stearic acid andsodium sulphate).

Administration is effected in the customary manner, preferably orally orparenterally, particularly perlingually or intravenously. In the case oforal use, the tablets can, of course, also contain, in addition to theexcipients mentioned, additives such as sodium citrate, calciumcarbonate and dicalcium phosphate, together with various additionalsubstances, such as starch, preferably potato starch, gelatine and thelike. Furthermore, lubricants, such as magnesium stearate, sodium laurylsulphate and talc, can be used concomitantly when making tablets. In thecase of aqueous suspensions, the active compounds can be mixed withvarious flavor -improving agents or colorants in addition to theabovementioned auxiliary substances.

In the case of parenteral use, solutions of the active compounds, usingsuitable liquid excipients, can be employed.

In general, it has proved advantageous, in the case of intravenousadministration, to administer amounts of about 0.001 to 1 mg/kg,preferably about 0.01 to 0.5 mg/kg, of body weight to achieve effectiveresults, and in the case of oral administration, the dosage is about0.01 to 20 mg/kg, preferably 0.1 to 10 mg/kg of body weight.

Nevertheless, it may be necessary, under certain circumstances, todeviate from the amounts mentioned, and in particular to do so as afunction of the body weight or of the nature of the administrationmethod, of the individual behavior towards the medicament, the nature ofits formulation, and the time or interval over which the administrationtakes place. Thus, it can in some cases be sufficient to manage withless than the abovementioned minimum amount, whereas in other cases theupper limit mentioned must be exceeded. In the case of administration oflarger amounts, it may be advisable to divide these into severalindividual administrations over the course of the day.

PREPARATION EXAMPLES

The respective R_(f) values listed were--if not otherwisenoted--determined by thin layer chromatography on silica gel (aluminumfoil, silica gel 60 F 254, E. Merck). The substance spot was visualizedby observation under UV light and/or by spraying with 1% strengthpotassium permanganate solution.

The flash chromatography was carried out on silica gel 60, 0.040-0.063mm, E. Merck (see Still et al., J. Org. Chem. 43, 2923, 1978; forsimpler separation problems, see Aldrichimica Acta 18, 25, 1985).Elution with solvent gradients means: starting with the pure, nonpolarsolvent mixture component, the polar eluant component is admixed to anincreasing extent, until the product desired is eluted (TLC check).

In the case of all products, the solvent was removed at about 0.1 torr.Hydrochlorides were stored overnight at this pressure over potassiumhydroxide/phosphorus pentoxide.

EXAMPLE 12-[4-Ethoxycarbonylamino-methyl)piperidin-1-yl]-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR48##

The solution of 1.70 g (9.0 mmol) of4-(ethoxycarbonylamino-methyl)-piperidine (obtained from4-amino-methyl-piperidine and diethyl carbonate in the presence of4-dimethylaminopyridine) in 18 ml of methanol was treated with 9.0 ml(9.0 mmol) of 1 N methanolic hydrochloric acid. After addition of 0.53 g(3.0 mmol) of 8-methoxy-2-tetralone, the mixture was stirred for afurther 5 minutes. 0.20 g (3.3 mmol) of sodium cyanoborohydride was thenadded and the mixture was stirred for 15 hours at room temperature,followed by standing for 18 days at about +4° C.

The reaction mixture was substantially concentrated in a rotaryevaporator, taken up in tert.-butyl methyl ether and stirred vigorouslyfor 30 minutes with dilute sodium hydroxide solution (pH of the aqueousphase was adjusted to 10). The aqueous phase was extracted carefullywith tert.-butyl methyl ether. Washing the combined organic phases withwater and saturated sodium chloride solution, drying over magnesiumsulphate, and concentrating in a rotary evaporator yielded the crudeproduct as an oil.

0.45 g (43%) of the title compound could be obtained as a yellowishsyrup by chromatography on silica

R_(f) (toluene/methanol 4:1): 0.38

IR (chloroform): 3460, 3003, 2920, 1681, 1587

EXAMPLE 22-[4-(Ethoxycarbonylamino-methyl)piperidin-1-yl[-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride of the compound from Example 1 was obtained bytreatment with ethereal hydrochloric acid. Melting point: 85° C.,vitrification, 105°-110° C., with decomposition.

EXAMPLE 38-Methoxy-2-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene##STR49##

1.76 g (10 mmol) of 8-methoxy-2-tetralone, 3.00 g (30 mmol) ofN-methylpiperazine and 1.80 g (30 mmol) of glacial acetic acid wererefluxed in 30 ml of methanol for 4 hours. 1.30 g (20 mmol) of sodiumcyanoborohydride were then added, and the mixture was refluxed for afurther hour. The reaction mixture was substantially concentrated in arotary evaporator, taken up in tert.-butyl methyl ether, and stirredvigorously for 30 minutes in 20% strength sodium hydroxide solution. Theaqueous phase was extracted carefully with tert.-butyl methyl ether.Washing the combined organic phases with water and saturated sodiumchloride solution, drying over potassium carbonate, and concentrating ina rotary evaporator yielded the crude product as an oil (2.9 g). Thiscrude product was combined with that obtained from a batch of equal size(this reaction was carried out in the presence of 3A molecular sieve,otherwise the same) and chromatographed on silica gel (toluene/methanol4:1). 4.20 g of the title compound were obtained in this fashion as abrownish oil (80%).

R_(f) (chloroform/methanol 2:1): 0.61

EXAMPLE 48-Methoxy-2-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalenedihydrochloride

The dihydrochloride was obtained as a virtually colorless solid from thecompound of Example 3 using ethereal hydrochloric acid.

Melting point: >265° C.

Analysis (C₁₆ H₂₄ N₂ O×2HCl×0.5 H₂ O): Calc. C 56.1 H 7.9 N 8.2 Cl 20.7:Found C 56.0 H 7.9 N 8.1 Cl 20.6:

EXAMPLE 52-(1-Ethoxycarbonylpiperidin-4-yl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR50##

The solution of 2.00 g (11.4 mmol) of 8-methoxy-2-tetralone, 2.90 g (17mmol) of 4-amino-1-ethoxycarbonylpiperidine and 3.40 g (57 mmol) ofglacial acetic acid in 80 ml of methanol was stirred at 0° C. for 30minutes. After addition of 3.85 g (45.6 mmol) of sodiumcyanoborohydride, the mixture was stirred for 3 hours at roomtemperature. The reaction mixture was substantially concentrated, takenup in toluene, reconcentrated, treated with tert.-butyl methyl ether,and stirred vigorously for 30 minutes with dilute sodium hydroxidesolution (pH of the aqueous phase adjusted to 10). The aqueous phase wasextracted carefully with tert.-butyl methyl ether. Washing the combinedorganic phases with water and saturated sodium chloride solution, dryingover potassium carbonate, and concentrating in a rotary evaporatoryielded the crude product as an oil.

After chromatography on silica gel (toluene/ethyl acetate gradients withaddition of 0.5% of triethylamine), 2.10 g (55%) of the title compoundwere obtained.

R_(f) (toluene/methanol 4:1): 0.26

IR (chloroform): 3005, 2931, 1679, 1587.

EXAMPLE 62-(1-Ethoxycarbonylpiperidin-4-yl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride, producible from the compound of Example 5 bytreatment with ethereal hydrochloric acid, precipitated as a colorlesssolid.

Melting point: >270° C.

Analysis C₁₉ H₂₈ N₂ O₃ ×HCl): Calc. : C 61.9 H 7.9 N 7.6 Cl 9.6: Found :C 61.3 H 8.0 N 7.6 Cl 9.4:

EXAMPLE 72-(3-Dimethylaminopropyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR51##

The solution of 7.04 g (40 mmol) of 8-methoxy-2-tetralone, 6.12 g (60mmol) of 3-dimethylamino-1-propylamine and 18 g (300 mmol) of glacialacetic acid was stirred at 0° C. for 30 minutes. After addition of 10.0g (160 mmol) of sodium cyanoborohydride, the mixture was stirred for 3hours at room temperature.

The reaction mixture was substantially concentrated in a rotaryevaporator, taken up in tert.-butyl methyl ether, and stirred vigorouslyfor 30 minutes with 20% strength sodium hydroxide solution. The aqueousphase was extracted carefully with tert.-butyl methyl ether. Washing thecombined organic phases with water and saturated sodium chloridesolution, drying over potassium carbonate, and concentrating in a rotaryevaporator yielded the crude product as an oil. The crude product waspurified by chromatography on silica gel (chloroform/methanol gradientswith addition of 1% of triethylamine). 5.10 g (49%) of the titlecompound were obtained in this fashion as a brown oil.

R_(f) (chloroform/methanol/triethylamine 20:10:0.1): 0.1

IR (chloroform): 3666, 3006, 1587, 1470

EXAMPLE 82-(3-Dimethylaminopropyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

The dihydrochloride of the compound of Example 7 could be obtained, inthe form of pale gray crystals, using ethereal hydrochloric acid.

Melting point: 173°-178° C.

EXAMPLE 92-(2-Diethylaminoethyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR52##

3.50 g (20 mmol) of 8-methoxy-2-tetralone, 4.60 g of2-diethylamino-1-ethylamine and 4.80 g (80 mmol) of glacial acetic acidin 150 ml of methanol were stirred at 0° C. for 30 minutes. Afteraddition of 5.00 g of sodium cyanoborohydride, the mixture was allowedto stand at room temperature for 15 hours.

The reaction mixture was substantially concentrated in a rotaryevaporator, taken up in tert.-butyl methyl ether, and stirred vigorouslyfor 30 minutes with 20% strength sodium hydroxide solution. The aqueousphase was extracted carefully with tert.-butyl methyl ether. Washing thecombined organic phases with water and saturated sodium chloridesolution, drying over potassium carbonate and concentrating in a rotaryevaporator yielded the crude product as an oil. Chromatography on silicagel (toluene/ethanol gradients) supplied 3.80 g (69%) of the titlecompound as a syrup.

R_(f) (chloroform/methanol) 2:1 ): 0.18

IR (chloroform, CHCl₃): 3282, 2970, 1586, 1470

EXAMPLE 102-(2-Diethylaminoethyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The dihydrochloride, obtained from the compound of Example 9 bytreatment with ethereal hydrochloric acid in ether, precipitated as abeige solid.

Melting point: 60° C., vitrification, about 100° C., decomposition

EXAMPLE 112-(2-Ethoxycarbonylamino-ethyl)amino-8-methoxy-1,2,3,4tetrahydronaphthalene##STR53##

10.0 g (159 mmol) of sodium cyanoborohydride were added to the solutionof 7.00 g (40 mmol) of 8-methoxy-2-tetralone, 8.00 g (61 mmol) ofN-(2-aminoethyl)ethylcarbamate and 9.60 g (160 mmol) of glacial aceticacid at 0° C. After 15 hours at room temperature, the mixture wasconcentrated, taken up in tert.-butyl methyl ether, and treated withwater. The pH of the aqueous phase was adjusted to 10 using sodiumhydroxide solution. The mixture was stirred vigorously for 30 minutes.The organic phase was separated off, and the aqueous phase was extractedthoroughly with the last-mentioned solvent. Drying the organic phase andconcentrating supplied an oil, which was purified by chromatography onsilica gel (toluene/ ethanol gradients with addition of 0.3%triethylamine). 5.40 g (46%) of the pure title compound were obtained asa brownish oil.

A further 6.00 g of the desired product were eluted, together withrelatively small amounts of relatively polar impurities (this fractionwas of adequate purity for further reactions).

R_(f) (toluene/methanol 4:1): 0.17

EXAMPLE 122-(2-Ethoxycarbonylamino-ethyl)amino-8-methoxy-1,2,3,4tetrahydronaphthalenehydrochloride

The hydrochloride was obtained from the pure product of Example 11 usingethereal hydrochloric acid. Melting point: 80° C. (with decomposition)

EXAMPLE 132-[N-(3-Dimethylaminopropyl)-N-propionyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR54##

3.3 g (25 mmol) of propionic anhydride and 22 ml of 3 N sodium hydroxidesolution were added to the mixture of 1.30 g (5 mmol) of2-(3-dimethylaminopropyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 35 ml of ether and 7 ml of water at 0° C. After stirring vigorouslyfor 1 hour, the same amount of propionic anhydride, and also 16 ml of 3N sodium hydroxide solution, were added again. After a further hour, afurther 2.5 g of propionic anhydride and 12 ml of 3 N sodium hydroxidesolution were added. After stirring for 15 hours at room temperature,the organic phase was separated off. The aqueous phase was extractedtwice with ether. The combined organic extracts were washed withsaturated sodium chloride solution, dried over magnesium sulphate, andfreed of solvent in vacuo. 1.20 g (75%) of the free base were thusobtained as a clear oil.

R_(f) (toluene/methanol 4:1): 0.22

IR (chloroform): 2981, 1626, 1588, 1469

MS: 318, 217, 190, 160

EXAMPLE 142-[N-(3-Dimethylaminopropyl)-N-propionyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride of the compound from

EXAMPLE 13 could be obtained as a foam using ethereal hydrochloric acid.

Analysis (C₁₉ H₃₀ N₂ O₂ ×HCl×H₂ O): Calc.: C 61.2 H 8.9 N 7.5. Found: C61.5 H 8.9 N 7.5.

EXAMPLE 152-[N-(2-Diethylaminoethyl)-N-acetyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR55##

2.2 g (22 mmol) of acetic anhydride and 20 ml of 3 N sodium hydroxidesolution were added to the mixture of 1.20 g (4.3 mmol) of2-(2-diethylaminoethyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene in35 ml of ether and 7 ml of water at 0° C. After stirring vigorously for1 hour the same amount of acetic anhydride, and also 15 ml of 3 N sodiumhydroxide solution, were added again. After a further hour, a further1.6 g of acetic anhydride and 12 ml of 3 N sodium hydroxide solutionwere added. After stirring for 15 hours at room temperature, the organicphase was separated off. The aqueous phase was extracted twice withether. The combined organic extracts were washed with saturated sodiumchloride solution, dried over magnesium sulphate, and freed of solventin vacuo. The crude product thus obtained was purified by chromatographyon silica gel (toluene/ethyl acetate gradients). This supplied 0.50 g(37%) of the title compound as a yellow oil.

R_(f) (toluene/methanol 4:1): 0.22

IR (chloroform): 3002, 2970, 1625, 1588, 1470

MS: 318, 246, 161

EXAMPLE 16

2-[N-(2-Diethylaminoethyl)-N-acetyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride of the compound from

EXAMPLE 15 could be precipitated as a colorless solid in ether usingethereal hydrochloric acid. Melting point: about 100° C., vitrification,about 150° C., with decomposition

Analysis (C₁₉ H₃₀ N₂ O₂ ×HCl): Calc.: C 64.3 H 8.8 N 7.9. Found: C 63.9H 8.8 N 7.9.

EXAMPLE 172-[N-(3-Dimethylaminopropyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR56##

The solution of 1.30 g (5.0 mmol) of2-(3-dimethylaminopropy)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene,2.90 g (50 mmol) of propionaldehyde and 1.50 g (25 mmol) of glacialacetic acid was stirred for 30 minutes at 0° C. After addition of 0.70 g(10 mmol) of sodium cyanoborohydride, the mixture was stirred for 15hours at room temperature. The reaction mixture was substantiallyconcentrated in a rotary evaporator, taken up in tert.-butyl methylether, and stirred vigorously for 30 minutes with 20% strength sodiumhydroxide solution. The aqueous phase was extracted carefully withtert.-butyl methyl ether. Washing the combined organic phases with waterand saturated sodium chloride solution, drying over potassium carbonate,and concentrating in a rotary evaporator yielded the desired compound asa clear oil. Yield: 1.50 g (98%)

R_(f) (chloroform/methanol/triethylamine 20:10:0.1): 0.26

IR (chloroform): 3040, 3007, 2936, 1653, 1587

MS: 304, 259, 232, 218, 204

EXAMPLE 182-[N-(3-Dimethylaminopropyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

Using ethereal hydrochloric acid, 1.3 g (70%) of dihydrochloride wereobtained from the compound of Example 17 as an amorphous, veryhygroscopic powder.

Analysis (C₁₉ H₃₂ N₂ O₂ ×2 HCl×H₂ O): Calc.: C 55.2 H 9.3 N 6.8 Cl17.2.Found: C 55.8 H 9.1 N 6.3 Cl 17.3.

EXAMPLE 192-[N-(2-Diethylaminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR57##

The solution of 1.20 g (4.3 mmol) of2-(2-diethyl-aminoethyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene,2.50 g (43 mmol) of propionaldehyde and 0.80 g (13 mmol) of glacialacetic acid was stirred for 30 minutes at 0° C. 1.10 g (17 mmol) ofsodium cyanoborohydride were subsequently added to the reaction mixture,which was stirred overnight at room temperature.

The reaction mixture was substantially concentrated in a rotaryevaporator, taken up in tert.-butyl methyl ether, and stirred vigorouslyfor 30 minutes with 20% strength sodium hydroxide solution. The aqueousphase was extracted carefully with tert.-butyl methyl ether. Washing thecombined organic phases with water and saturated sodium chloridesolution, drying over potassium carbonate and concentrating in a rotaryevaporator yielded the crude product as an oil.

Chromatography on silica gel (toluene/ethyl acetate gradients) yielded0.85 g (62%) of the title compound as a yellow oil.

R_(f) (toluene/methanol 4:1): 0.17

MS 318, 232, 161

IR (chloroform): 3058, 2972, 1586

EXAMPLE 202-[N-(2-Diethylaminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4tetrahydronaphthalenedihydrochloride

The dihydrochloride, produced from the compound of Example 19 bytreatment with ethereal hydrochloric acid, precipitated as an amorphoussubstance and was very hygroscopic.

Analysis (C₂₀ H₃₄ N₂₀ ×2 HCl×2 H₂ O): Calc.: C 56.2 H 9.4 N 6.6. Found:C 56.7 H 9.4 N 6.5.

EXAMPLE 212-[N-(2-Ethoxycarbonylamido-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR58##

5.09 g (20 mmol) of2-(2-ethoxycarbonylamido-ethyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene,11.6 g (200 mmol) of propionaldehyde and 2.40 g (40 mmol) of glacialacetic acid were stirred for 30 minutes at 0° C. in 150 ml of methanol.2.50 g (40 mmol) of sodium cyanoborohydride were then added, and themixture was stirred for 15 hours at room temperature.

The reaction mixture was substantially concentrated in a rotaryevaporator, taken up in tert.-butyl methyl ether, and stirred vigorouslyfor 30 minutes with sodium hydroxide solution/water at pH 10. Theaqueous phase was extracted carefully with tert.-butyl methyl ether.Washing the combined organic phases with water and saturated sodiumchloride solution, drying over magnesium sulphate, and concentrating ina rotary evaporator yielded the crude product as an oil. The crudeproduct obtained was chromatographed on silica gel (toluene/ethanolgradients). 5.20 g (78%) of the desired compound were thus obtained as apale brown oil.

R_(f) (toluene/methanol 4:1): 0.25

IR (chloroform, CHCl₃): 3403, 2931, 1702, 1585

EXAMPLE 222-[N-(2-Ethoxycarbonylamido-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride was produced as a foam from the compound of

EXAMPLE 21 using ethereal hydrochloric acid.

MS (C.I., reagent gas: NH3): 335, 289, 232, 161

EXAMPLE 232-(N-Quinuclidin-3-yl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR59##

1.60 g (5.6 mmol) of2-(quinuclidin-3-yl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene(obtained from 8-methoxy-2-tetralone and 3-aminoquinuclidine byreductive amination in the conventional fashion), 3.20 g (56 mmol) ofpropionaldehyde and 1.70 g (28 mmol) of glacial acetic acid were stirredfor 30 minutes at 0° C. 0.80 g (11 mmol) of sodium cyanoborohydride wasthen added, and the mixture was stirred for 15 hours at roomtemperature. The reaction mixture was concentrated, taken up in tolueneand reconcentrated, taken up in tert.-butyl methyl ether, and stirredvigorously for 30 minutes with 20% strength sodium hydroxide solution.The aqueous phase was extracted carefully with tert.-butyl methyl ether.Washing the combined organic phases with water and saturated sodiumchloride solution, drying over potassium carbonate, and concentrating ina rotary evaporator yielded the crude product as an oil (2.0 g).Chromatography on silica gel (toluene/ethanol 3:1) supplied the titlecompound as a syrup.

Yield: 0.50 g (27%).

R_(f) (chloroform/methanol 2:1): 0.13

MS: 328, 216, 168, 160

EXAMPLE 242-(N-Quinuclidin-3-yl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

The dihydrochloride was precipitated in the form of colorless crystalsfrom the ethereal solution of the compound of

EXAMPLE 23 using ethereal hydrochloric acid.

Melting point: 200°-205° C.

EXAMPLE 252-(N-Cyanomethyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR60##

3.2 g (15 mmol) of8-methoxy-2-propylamino-1,2,3,4-tetrahydronaphthalene, 5.6 g (72 mmol)of chloroacetonitrile and 9.6 g (72 mmol) of potassium carbonate weresuspended in 65 ml of 2-butanone, 80 mg of sodium iodide were added, andthe mixture was stirred overnight at 60° C. After filtration throughCelite, the mixture was freed of solvent (rotary evaporator). Afterchromatography on silica gel (toluene/ethyl acetate gradients), 3.65 g(98%) of a pale yellow oil were obtained.

R_(f) (toluene/methanol 4:1): 0.81

MS: 258, 229, 161

EXAMPLE 262-(N-Cyanomethyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride was obtained, as colorless crystals, from the freebase (Example 25) using ethereal hydrochloric acid.

Melting point: 164°-166° C.

EXAMPLE 278-Methoxy-2-[N-propyl-N-(3-phthalimidoyl-propyl)]amino-1,2,3,4-tetrahydronaphthalene##STR61##

1.55 g (7.0 mmol) of8-methoxy-2-N-propylamino-1,2,3,4-tetrahydronaphthalene, 1.40 g (14mmol) of triethylamine, 1.90 g (7.0 mmol) ofN-(3-bromopropyl)phthalimide and a spatula tip of sodium iodide werestirred for hours at 60° C. in 35 ml of absolute dimethylformamide.After stripping off the solvent in a rotary evaporator (finally at 0.2torr), the main product was obtained, as a yellowish oil, by flashchromatography on silica gel (toluene/ethyl acetate gradients, 0-33%ethyl acetate).

Yield: 0.90 g

R_(f) (toluene/ethyl acetate 1:1): 0.12

EXAMPLE 288-Methoxy-2-[N-propyl-N-(3-phthalimidoyl-propyl)]amino-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride was obtained, as a colorless hygroscopic solid, from

EXAMPLE 27 using ethereal hydrochloric acid.

Yield: 0.58 g

Melting point: 80°-100° C.

EXAMPLE 292-[N-(N,N-Diethylcarbamoylmethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR62##

0.80 g (3.7 mmol) of8-methoxy-2-propylamino-1,2,3,4-tetrahydronaphthalene, 2.75 g (18 mmol)of chloroacetic diethylamide, 2.50 g (18 mmol) of powdered potassiumcarbonate and 30 mg of sodium iodide in 10 ml of 2-butanone were reactedat 60° C. The reaction mixture was diluted with 100 ml of tert.-butylmethyl ether. Undissolved material was filtered off, and the solvent wasremoved. The residue remaining here was taken up in tert.butyl methylether. After acidification, the organic phase was separated off anddiscarded. The aqueous phase was basified and extracted with thelast-mentioned solvent. After drying and concentrating the organicphase, 1.2 g of crude product remained as a brown oil.

R_(f) (toluene/methanol 4:1): 0.5

MS (C.I. spectrum, reagent gas NH₃): 333 (M+1), 232, 161

EXAMPLE 302-[N-(N,N-Diethylcarbamoylethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

795 mg (58%) of hydrochloride were obtained as a a pale brown solid fromthe crude product of Example 29 using ethereal hydrochloric acid.

MS (C.I., reagent gas: NH₃): 333 (M+1), 252, 161.

EXAMPLE 312-(N-Ethoxycarbonylmethyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR63##

2.6 g (12 mmol) of8-methoxy-2-propylamino-1,2,3,4-tetrahydronaphthalene, 1.7 g (12 mmol)of potassium carbonate, 6.0 g of molecular sieve (3A), 2.0 g (12 mmol)of ethyl bromoacetate and 100 mg of sodium iodide in 42 ml of ethanolwere refluxed for 2 hours. After this time, a further 0.25 equivalentsof potassium carbonate and 0.25 equivalents of ethyl bromoacetate wereadded, and the mixture was refluxed for a further 2 hours. Filtrationthrough Celite and concentration supplied a crude product, which waspurified by chromatography on silica gel (toluene/ ethyl acetategradients). In this fashion, 3.5 g of a colourless syrup (according toNMR, still contained about 4% of toluene) were obtained.

R_(f) (toluene/methanol 4:1): 0.79

IR (chloroform): 1736, 1587, 1378, 1255

EXAMPLE 322-(N-Ethoxycarbonylmethyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

580 mg of hydrochloride were obtained as a colorless, amorphous,hygroscopic solid of 600 mg of the free base from Example 31 bytreatment with ethereal hydrochloric acid.

Analysis (C₁₈ H₂₇ NO₃ ×HCl×H2O): Calc.: C 60.0 H 8.3 N 3.9. Found: C60.0 H 8.4 N 3.7.

EXAMPLE 332-{4-[N-(8-Methoxy-1,2,3,4-tetrahydro-2-naphtyl)-N-propylamino]butyl}-1,2-benzisothiazol-3(2H)-one1,1-dioxide ##STR64##

1.9 g (6.0 mmol) of 2-(4-bromobutyl)-1,2-benzisothiazol-3(2H)-one1,1-dioxide were added dropwise to the solution of 1.3 g (6.0 mmol) of8-methoxy-2-propylamino-1,2,3,4-tetrahydronaphthalene and 1.3 g (12mmol) of triethylamine in 15 ml of dimethylformamide. After stirring for15 hours at room temperature, a spatula tip of sodium iodide was added,and the mixture was heated to 60° C. After 4 hours at this temperature,0.4 g of the above aminotetralin and 0.3 g of triethylamine were added.Chromatography on silica gel (toluene/ethyl acetate gradients) of thecrude product, obtained after removal of the solvent in vacuo, yielded0.70 g (25%) of the title compound as a yellowish oil.

R_(f) (toluene/ethyl acetate 1:1): 0.36

MS: 456, 427, 232, 219, 196, 190, 161.

EXAMPLE 342-{4-[N-(8-Methoxy-1,2,3,4-tetrahydro-2-naphthyl)-N-propyl-amino]butyl}-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride

The hydrochloride was obtained as a colorless solid by treatment of thecompound of Example 33 with ethereal hydrochloric acid.

Melting range: 65°-80° C.

EXAMPLE 35 2-[N-(3-Aminopropyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR65##

A solution of 12.2 g (45 mmol) of2-[N-(2-cyano-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 20 ml of ether was added carefully to 135 mmol of aluminum hydride in100 ml of ether (prepared at 0° C. from 5.1 g of lithium aluminumhydride and a mixture ©f 3.3 g of 95% strength sulphuric acid and 3.3 gof 20% strength oleum in ether, with subsequent stirring for 1 hour atroom temperature) at room temperature. The mixture was refluxed for 2hours, and subsequently stirred for 15 hours at room temperature. Afteraddition of 30 ml of water and 60 ml of 10% strength sodium hydroxidesolution, the organic phase was separated off from the voluminousprecipitate. The latter was leached three times with boiling ether.Drying the organic phase (potassium carbonate) and evaporation of thesolvent yielded 9.30 g (75%) of a brown, viscous oil.

R_(f) (chloroform/methanol/ammonia 30:10:1): 0.52

MS: 276, 247, 232

EXAMPLE 36(2-Aminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR66##

A mixture of 0.9 g of 95% strength sulphuric acid and 0.9 g of 20%strength oleum was added slowly to 1.4 g (13 mmol) of lithium aluminumhydride in 25 ml of ether at 0° C. After stirring for 1 hour at roomtemperature, a solution of 3.1 g (12 mmol) of2-(N-cyanomethyl-N-propyl)-amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 5 ml of ether was added dropwise. The mixture was refluxed for hours.10 ml of water were then added carefully, followed by 20 ml of 10%strength sodium hydroxide solution. The undissolved material wasseparated off; this solid was washed several times with ether. Afterdrying the organic phase over sodium carbonate and after removal of thesolvent in vacuo (finally high vacuum), 2.3 g (73%) of the titlecompound were obtained as an oil.

R_(f) (chloroform/methanol 2:1 +1% triethylamine): 0.1

MS (C.I., reagent gas: NH3): 263, 232, 161

EXAMPLE 372-[N-(2-aminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride

1.3 g of dihydrochloride were obtained as a colorless solid by treatmentof 1.0 g of the free base from Example 36 with ethereal hydrochloricacid. Melting point: from 73° C., vitrification

EXAMPLE 388-Methoxy-2-[N-(2-methoxylaminoethyl)-N-propyl]amino-1,2,3,4-tetrahydronaphthalene##STR67##

3.40 g (10 mmol) of2-[N-(2-ethoxycarbonylamidoethyl)-N-propyl]-amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 25 ml of ether were slowly added dropwise to the suspension of 0.75 g(20 mmol) of lithium aluminum hydride in 25 ml of ether at roomtemperature. After stirring overnight, the mixture was diluted with 15ml of ether. 1 ml of water, 0.75 ml of sodium hydroxide solution and 3.0ml of water were subsequently carefully added successively. For drying,10 g of potassium carbonate were added, and the mixture was stirred for20 minutes. Filtration and concentration supplied 2.7 g of crudeproduct. Chromatography on silica gel (chloroform/ methanol gradients),twice, yielded 0.60 g (33%) of the title compound as a colorless syrup.

R_(f) (chloroform/methanol/triethylamine 2:1:0.01): 0.29

EXAMPLE 398-Methoxy-2-[N-(2-methylaminoethyl)-N-propyl]amino-1,2,3,4-tetrahydronaphthalenedihydrochloride

The dihydrochloride, produced as a very hygroscopic, amorphous,colorless solid, was obtained from the compound of

EXAMPLE 38 by treatment with ethereal hydrochloric acid.

Analysis (C₁₇ H₂₈ N₂ O×2 HCl×H2O): Calc. C 55.6 H 8.8 N 7.6. Found C55.4 H 8.7 N 7.3.

EXAMPLE 408-Methoxy-2-(1-methylpiperidin-4-yl)amino-1,2,3,4-tetrahydronaphthalene##STR68##

A solution of 1.20 g (3.6 mmol) of2-(1-ethoxy-carbonyl-piperidin-4-yl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 10 ml of ether was added dropwise at room temperature to thesuspension of 0.27 g (7.2 mmol) of lithium aluminum hydride in 10 ml ofether. After stirring &for 15 hours at room temperature, the mixture wasdiluted with 30 ml of ether. 0.3 ml of water, 0.25 ml of 20% strengthsodium hydroxide solution and 1 ml of water were subsequently carefullyadded dropwise. For drying, 3 g of potassium carbonate were added, andthe mixture was stirred for 20 minutes. By filtration and concentration(finally high vacuum), U.90 g (91%) of the title compound was obtainedas an oil.

R_(f) (chloroform/methanol/triethylamine 20:10:0.1): 0.26

EXAMPLE 418-Methoxy-2-(1-methylpiperidin-4-yl)amino-1,2,3,4-tetrahydronaphthalenedihydrochloride

The dihydrochloride, obtained by reaction of the compound from Example40 with ethereal hydrochloric acid, precipitated in the form of paleyellow crystals.

Melting point: >260° C.

Analysis (C₁₇ H₂₆ N₂ O×2 HCl×H₂ O): Calc.: C 56.2 H 8.3 N 7.7. Found: C55.9 H 8.2 N 7.7.

EXAMPLE 422-[N-(2-Hydroxyethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR69##

2.9 g (9.5 mmol of2-(N-ethoxycarbonylethyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 20 ml of ether were added dropwise to the suspension of 0.22 g (5.7mmol) of lithium aluminium hydride in 10 ml of ether. After stirring for1 hour at room temperature, 0.3 ml of water, 0.35 ml of 20% strengthsodium hydroxide solution and 1.0 ml of water were added successively.Drying agent (magnesium sulphate) was added, and the mixture was stirredfor 20 minutes at room temperature, filtered through Celite, and freedof solvent in vacuo (finally in a high vacuum). 1.8 g (72%) of a clearoil remained.

R_(f) (toluene/ethanol 6:1): 0.25

MS: 263, 232, 161

IR (chloroform): 3670, 3430, 1587

EXAMPLE 432-[N-(2-Carbamoylethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR70##

0.54 g (2 0 mmol) of2-[N-(2-cyanoethyl)-N-propyl]-amino-8-methoxy-1,2,3,4-tetrahydronaphthalenewere stirred for 2 hours at room temperature with 2 ml of concentratedhydrochloric acid. After dilution with 20 ml of water, the mixture wasadjusted to pH 7 using 20% strength sodium hydroxide solution, withcooling, and the aqueous phase was extracted carefully with ethylacetate. The crude product, obtained after drying and concentrating theorganic phase, was purified by chromatography on aluminum oxide(neutral, activity III) using toluene/ ethyl acetate gradients.

R_(f) (aluminum oxide, toluene/ethyl acetate 1:1): 0.1

MS: 290, 261, 232, 161

EXAMPLE 442-[N-(2-Carbamoylethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride was obtained, as a colorless solid, from the compoundof Example 43 by treatment with ethereal hydrochloric acid in ether.

Melting point: 80° C. (vitrification from 65° C.)

EXAMPLE 458-Methoxy-2-{N-[2-(4-toluene-sulphonamido)ethyl]-N-propyl}amino-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR71##

0.77 g (4.0 mmol) of tosyl chloride in 5 ml of dichloromethane was addeddropwise to the solution of 1.00 g (4.0 mmol) of2-[N-(2-amino-ethyl)-N-propyl]amino8-methoxy-1,2,3,4-tetrahydronaphthalenein 10 ml of dichloromethane at 0° C. After stirring for 15 hours at roomtemperature, the mixture was freed of solvent in vacuo. Digestion of theresidue in ether yielded 1.6 g of the hydrochloride of the titlecompound as a yellowish, microcrystalline solid.

Melting range: from 100° C., with decomposition,

EXAMPLE 468-Methoxy-2-{N-[2-(4-toluene-sulphonamido)ethyl]-N-propyl}amino-1,2,3,4-tetrahydronaphthalene

The free base is obtained by treatment of the compound from Example 45with sodium bicarbonate solution.

R_(f) (toluene/ethanol 3:1): 0.53

EXAMPLE 472-{N-[3-(4-Fluorophenylsulphonamido)propyl]-N-propyl}-amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR72##

0.39 g (2.0 mmol) of 4-fluorophenylsulphonyl chloride in 5 ml ofmethylene chloride was added dropwise to the solution of 0.55 g (2.0mmol) of2-[N-(3-aminopropyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 8 ml of methylene chloride at 0° C. After stirring for 15 hours atroom temperature, the mixture was concentrated and the hydrochloride wasprecipitated, in the form of beige crystals, from ethanolic solution byaddition of ether.

Yield: 0.82 g (94%)

Melting range: 120°-140° C. (after vitrification)

MS: 434, 405, 232, 219, 186, 161

EXAMPLE 482-{N-[3-(4-Fluorophenylsulphonamido)propyl]-N-propyl}-amino-8-methoxy-1,2,3,4-tetrahydronaphthalene

The free base was obtained by treatment of the compound of

EXAMPLE 47 with sodium bicarbonate solution.

R_(f) (toluene/ethanol 3:1): 0.45

EXAMPLE 492-[N-(2-Methanesulphonamidoethyl)-N-propyl]amino-8-methxoy-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR73##

230 mg (2.0 mmol) of methanesulphonyl chloride in 2 ml of methylenechloride were added dropwise to the solution of 520 mg (2.0 mmol) of2-[N-(2-aminoethyl)-N-propyl]-amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 5 ml of methylene chloride at 0° C. After stirring for 15 hours atroom temperature, the mixture was freed of solvent in a rotaryevaporator at a maximum bath temperature of +25° C. Digestion of theresidue with diethyl ether yielded 673 mg (89%) of hydrochloride afterdrying the solid in a high vacuum.

Melting point: from 100° C., with decomposition.

MS (C.I., reagent gas: NH3): 341 (M+1), 232, 161

EXAMPLE 502-N-(2-Methanesulphonamidoethyl)-N-propyl]-8-methoxy-1,2,3,4-tetrahydronaphthalene

The free base was obtained by treatment of the compound of Example 49with sodium bicarbonate solution.

R_(f) (chloroform/methanol 2:1): 0.65

EXAMPLE 512-{N-[2-(3-Chloropropylsulphonamido)ethyl]-N-propyl}-amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR74##

1.80 g (10 mmol) of 3-chloropropanesulphonyl chloride in 20 ml ofdichloromethane were slowly added dropwise, at 0° C. to the solution of2.70 g (10 mmol) of2-[N-(2-aminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene50 ml of dichloromethane, excluding moisture. After 15 hours at roomtemperature, the mixture was diluted with 150 ml of ethyl acetate and 50ml of water. The pH was adjusted to 7 using sodium hydroxide solution.Extraction with ethyl acetate, washing of the organic phase withsaturated sodium chloride solution, and drying over magnesium sulphateyielded 4.3 g of crude product, after evaporation of the solvent.

Flash chromatography on silica gel (toluene/ethyl acetate gradients)supplied 4.10 g of pure product, still slightly contaminated by solvent.

R_(f) (toluene/ethanol 3:1): 0.62

IR (chloroform): 3319, 3019, 2961 1587 1470

MS (C.I., reagent gas: NH₃): 405/403 (M+1), 367, 232, 161

EXAMPLE 522-{N-[2-(3-Chloropropylsulphonamido)ethyl]-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride was obtained, in a yield of 92%, as a pale yellowish,hygroscopic solid, from the free base of Example 51 using etherealhydrochloric acid.

Melting range: 60°-70° C.

EXAMPLE 532-{N-[2-(4-Chlorobutanesulphonamido)ethyl]-N-propyl}-amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR75##

2.00 g 10 mmol) of 4-chlorobutanesulphonyl chloride in 20 ml ofdichloromethane were slowly added dropwise to the solution of 2.70 g (10mmol) of 2-[N-(2aminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene in 50ml of dichloromethane at 0° C., excluding moisture. After 15 hours atroom temperature, the mixture was diluted with 150 ml of ethyl acetateand 50 ml of water. The pH of the mixture was adjusted to 7 using sodiumhydroxide solution. Extraction with ethyl acetate, washing of theorganic phase with saturated sodium chloride solution and drying overmagnesium sulphate yielded 4.5 g of crude product, after evaporation ofthe solvent.

Flash chromatography on silica gel (toluene/ethyl acetate gradients)gave 3.2 g (77%) of the title compound as a syrup.

R_(f) (toluene/ethanol/triethylamine 30:10:0.5): 0.46

IR (chloroform): 3296, 3010, 2964, 1587, 1470

MS (C.I., reagent gas: NH3): 419/417 (M+1), 381, 232, 161

EXAMPLE 542-{N-[2-(4-Chlorobutanesulphonamido)ethyl]-N-propyl}-amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride was obtained, as a pale yellowish, hygroscopic solid,from the free base (compound 53) using ethereal hydrochloric acid.

Melting point: 70° C.

EXAMPLE 552-{2-[N-propyl-N-(8-methoxy-1,2,3,4-tetrahydro-2-naphthyl)]amino}ethyl-isothiazolidine1,1-dioxide ##STR76##

1.60 g (4.0 mmol) of2-{N-[2-(3-chloropropylsulphonamido)ethyl]-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 3 ml of dimethylformamide were added to the suspension of 144 mg (4.8mmol) of sodium hydride (80% strength in paraffin) and a spatula tip ofsodium iodide in 20 ml of dimethylformamide. After stirring for 1 hourat room temperature, 0.3 ml of water was added. After concentrating in arotary evaporator, the mixture was distributed between toluene andwater. 1.2 g (82%) of the title compound were obtained as an oil bythorough extraction, drying over magnesium sulphate and concentrating.

R_(f) (toluene/ethyl acetate 1:1): 0.28

MS (C.I., reagent gas: NH3): 367 (M+1) 232

EXAMPLE 562-{2-[N-Propyl-N-(8-methoxy-1,2,3,4-tetrahydro-2-naphthyl)]amino}ethyl-isothiazolidine1,1-dioxide hydrochloride

The hydrochloride of the compound of Example 55 was obtained as acolorless hygroscopic solid by treatment with ethereal hydrochloric acidin ether

Melting point: 90°-100° C..

EXAMPLE 572-[2-N-Propyl-N-(8-methoxy-1,2,3,4-tetrahydro-2-naphthyl)amino]ethyl-perhydro-1,2-thiazine1,1-dioxide ##STR77##

1.46 g (3.5 mmol) of2-{N-[2-(4-chlorobutanesulphonamido)ethyl]-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 7 ml of dimethylformamide were added to the suspension of 126 mg (4.2mmol) of sodium hydride (80% strength in paraffin) and 175 mg (1.1 mmol)of sodium iodide in 18 ml of dimethylformamide. After stirring for 1hour at room temperature, 0.1 ml of water was added. After concentratingin a rotary evaporator, the mixture was distributed between toluene andwater. 1.2 g (90%) of the title compound was obtained as an oil bythorough extraction, drying over magnesium sulphate and concentrating.

R_(f) (toluene/ethyl acetate 1:1): 0.4

MS (C.I., reagent gas: NH3): 381 (M+1) 232 161

EXAMPLE 582-[2-N-Propyl-N-(8-methoxy-1,2,3,4-tetrahydro-2-naphthyl)amino]ethyl-perhydro-1,2-thiazine1,1-dioxide hydrochloride

The hydrochloride was obtained, as a colorless hygroscopic solid, bytreatment of the compound of Example 57 with ethereal hydrochloric acidin ether

Melting point: 80°-90° C.

EXAMPLE 592-{N-[2-(N,N-Dimethylaminosulphonamido)]ethyl-N-propyl}-amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR78##

0.30 g (2.0 mmol) of dimethylamidcsulphonyl chloride in 5 ml ofanhydrous methylene chloride was slowly added dropwise at 0° C. to thesolution of 0.53 g (2.0 mmol) of2-[N-(2-aminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 8 ml of anhydrous methylene chloride. After stirring overnight, themixture was diluted with 50 ml of ethyl acetate and 30 ml of water, thepH was adjusted to 7 using sodium hydroxide solution, and the organicphase was separated off. Drying the organic phase (magnesium sulphate)and concentrating supplied 0.6 g of crude product.

Flash chromatography on silica gel (toluene/ethyl acetate gradients)yielded 0.38 g (52%) of the title compound as a colorless syrup.

R_(f) (toluene/ethanol triethylamine 30:10:0.5): 0.47

IR (chloroform): 3009, 2929, 1584, 1468 1372

MS (C.I., reagent gas: NH3): 370 (M+1) 232 153 121

EXAMPLE 602-{N-[2-(N,N-Dimethylaminosulphonamido)]ethyl-N-propyl}-amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride of the compound 59 is obtained as a hygroscopic solidusing ethereal hydrochloric acid.

Melting point: 65°-70° C.

EXAMPLE 618-Methoxy-2-[N-propyl-N-(2-nicotinoylamido-propyl)]amino-1,2,3,4-tetrahydronaphthalene##STR79##

20 mg of sodium hydride suspension (80% strength in paraffin) were addedto the solution of 0.55 g (2.0 mmol) of2-(N-3-aminopropyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthaleneand 0.28 g (2.0 mmol) of methyl nicotinate in 20 ml of tetrahydrofuran,and the mixture was refluxed for 5 hours. The solvent was removed in arotary evaporator. The remaining residue was taken up in 30 ml oftoluene and 30 ml of ice-cold pH 7 buffer. Phase separation, extractionof the aqueous phase with ethyl acetate, drying the combined organicphases over magnesium sulphate, and evaporation of the solvent yielded680 mg of crude product. This crude product was purified by flashchromatography on silica gel (eluent: toluene, toluene/ethyl acetate 1:1and toluene/ethanol 5:1). 520 mg (76%) of the title compound wereobtained as a brownish syrup.

R_(f) (HPTLC prepared plate NH₂ F254s, Merck; toluene/ ethyl acetate1:1): 0.3

EXAMPLE 628-Methoxy-2-[N-propyl-N-(2-nicotinoylamido-propyl)]amino-1,2,3,4-tetrahydronaphthalenedihydrochloride

The dihydrochloride was obtained, as a colorless, hygroscopic solid,from the compound of Example 61 using ethereal hydrochloric acid.

Melting point: 110° C.

EXAMPLE 63 N-6-Chlorohexyl-N'-{3-[N-(8-methoxy-1,2,34-tetrahydro-2-naphthyl)-N-propyl]aminopropyl}-urea ##STR80##

330 mg (2.0 mmol) of 6-chlorohexyl isocyanate in 3 ml of tetrahydrofuranwere slowly added dropwise, at 0° C., to the solution of 550 mg (2.0mmol) of2-[N-(3-aminopropyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 10 ml of anhydrous tetrahydrofuran. After 1 hour at 0° C., themixture was stirred for a further 1 hour at room temperature. The crudeproduct, obtained after evaporation of the solvent, was purified byflash chromatography on silica gel (toluene/methanol gradients). Yield:950 mg of a yellowish syrup (still contained residual solvent)

R_(f) (toluene/methanol 4:1): 0.26

MS: 439/437, 410/408, 396/394, 372, 232, 161

EXAMPLE 64N-6-Chlorohexyl-N'-{3-[N-(8-methoxy-1,2,3,4-tetrahydro-2-naphthyl)-N-propyl]aminopropyl}ureahydrochloride

Treatment of the compound from Example 64 with ethereal hydrochloricacid supplied the hydrochloride as a colorless, amorphous solid (795mg).

¹ H NMR (CD₃ OD):=1.05 (t, 2H); 1.25-2.05 (m, 13H); 2.30 (m, 1H); 2.78(m, 1H); 2.9-3.6 (m); 3.75 (m, 1H); 3.85 (s, 3H); 6.7 (m, 2H); 7.15 (m,1H).

EXAMPLE 65N-{2-[N-(8-Methoxy-1,2,3,4-tetrahydro-2-naphthyl)-N-propyl]aminoethyl}-N'-phenyl-urea##STR81##

0.50 g (1.91 mmol) of2-[N-(2-aminoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenewas dissolved in 10 ml of tetrahydrofuran, and 0.23 g (1.92 mmol) ofphenyl isocyanate in the same amount of tetrahydrofuran were slowlyadded at 0° C. After 1 hour at 0° C. and 1 hour at room temperature, themixture was concentrated. The crude product was purified by flashchromatography on silica gel (toluene/methanol gradients). 0. 60 g (82%)of the title compound were thus obtained as a syrup.

R_(f) (toluene/ethanol/triethylamine 3:1:0.05): 0.35

IR (chloroform): 3430, 3360, 3030, 1666

MS (FAB): 382 (M+1), 232, 161

EXAMPLE 66N-{2-[N-(8-Methoxy-1,2,3,4-tetrahydro-2-naphthyl)-N-propyl]aminoethyl}-N'-phenyl-ureahydrochloride

The hydrochloride was obtained, as an amorphous, hygroscopic solid, fromthe free base of Example 65 using ethereal hydrochloric acid.

Analysis (C₂₃ H₃₁ N₃ O₂ ×HCl×H₂ O): Calc.: C 63.5 H 7.8 N 9.6. Found: C64.0 H 7.8 N 10.1.

EXAMPLE 672-[N-(2-Ethyl-carbonyldioxy-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR82##

A solution of 0 50 g (4.4 mmol) of ethyl chloroformate in 15 ml ofmethylene chloride was added dropwise at 0° C. to the solution of 0.70 g(8.8 mmol) of pyridine and 1.10 g (4.0 mmol) of2-[N-(2-hydroxyethyl)-N-propyl]-amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 20 ml of methylene chloride. After stirring for 15 hours at roomtemperature, the mixture was filtered, and the organic phase was washedwith water and saturated sodium chloride solution. Drying (magnesiumsulphate) and concentrating supplied 0.8 g of crude product.Chromatography on silica gel (toluene/ethyl acetate gradients) gave 0.25g (19%) of the title compound.

R_(f) (toluene/ethyl acetate 3:1): 0.56

MS 335, 306, 232, 176, 161

EXAMPLE 682-[N-(2-Ethyl-carbonyldioxy-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride of the compound from Example 67 can be obtained as acolorless, amorphous solid using ethereal hydrochloric acid.

¹ H NMR (CD₃ OD):=1.05 (t, 3H); 1.38 (t, 3H); 1.82 (m, 3H); 2.35 (m,1H); 2.7-3.85 (m); 4.25 (q, 2H); 4.5 (m, 2H); 6.75 (m, 2H); 7.15 (m,1H).

EXAMPLE 692-[N-(2-Cyanoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR83##

1.10 g (5.0 mmol) of8-methoxy-2-propylamino-1,2,3,4-tetrahydronaphthalene, 1.30 g (25 mmol)of acrylonitrile and 20 mg of copper acetate were stirred for 3.5 hoursat 100° C. Flash chromatography of the reaction batch on silica gel(toluene/ethyl acetate gradient) yielded 1.10 g (81%) of the titlecompound as a yellowish oil.

R_(f) (toluene/ethyl acetate 3:1): 0.62

MS 272, 243, 232, 161

IR (chloroform): 2249, 1587

EXAMPLE 702-[N-(2-Cyanoethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride was obtained, as a colorless solid, from the compoundof Example 69 using ethereal hydrochloric acid.

Melting range.: 60°-67° C.

The following was prepared analogously to

EXAMPLES 1 to 12: EXAMPLE 712-[3-(Indol-3-yl)propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR84##

Melting point: 154° C.

The following were prepared analogously to Example 17 to 24;

EXAMPLE 722-N-Propyl-N-[3-(1,2,3,4-tetrahydronaphthalen-1-yloxy)-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride (diastereomeric mixture) ##STR85##

¹ H NMR (CD₃ OD): δ=1.0 (m, 3H); 1.6-2.3 (m, 10 H); 2.6-3.9 (m); 4.5 (m,1H); 6.7 (2d, 2H); 7.0-7.4 (m, 5H).

EXAMPLE 732-}N-[3-(Indol-3-yl)propyl]-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride ##STR86##

Melting range: 70°-130° C. (hygroscopic)

¹ H NMR (CD₃ OD): δ=0.95 (t, 3H); 1.6-1.9 (m, 3H); 2.1-2.2 (m, 3H);2.6-3.75 (m); 3.8 (s, 3H); 6.7 (2d, 2H); 6.9-7.1 (m); 7.35 (d, 1H); 7.55(d, 1H).

EXAMPLE 742-{N-[2-(Indol-3-yl)ethyl]-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalenedihydrochloride ##STR87##

Melting point: >100° C.

¹ H NMR (CD₃ OD): δ=1.05 (t, 3H); 1.7-2.0 (m, 3H); 2.3 (m, 1H); 2.7-3.9(m, ); 6.6-6.8 (m, 2H); 7.0 (m, 3H); 7.25 (d, 1H); 7.4 (d, 1H); 7.6 (dd,1H).

EXAMPLE 752-[N-(3-Phenylthio-propyl)-N-propyl)amino-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR88##

¹ H NMR (CD3OD): δ=1.0 (d, 3H); 1.6-1.9 (m, 3H); 2.1 (m, 2H); 2.25 (m,1H); 2.1-3.5 (m); 3.65 (m, 1H); 3.8 (s, 3H); 6.7 (d, 1H); 6.75 (d, 1H);7.15 (dd, 1H); 7.15-7.4 (m, 5H).

The following were prepared analogously to Example 25 to 34:

EXAMPLE 762-[N-4-(4,4-Dimethyl-2,6-dioxo-piperidin-1-yl)butyl-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR89##

¹ H NMR (CD₃ OD): δ=1.0-1.1 (m, 9H); 1.6-2.0 (m, 7H) 2.3 (m, 1H); 2.55(s, 4H); 2.8-3.9 (m); 6.85 (2d, 2H), 7.1 (dd, 1H).

EXAMPLE 772-{3-[N-(8-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-amino]propyl}-1,2-benzisothiazol-3(2H)-one1 1dioxide hydrochloride ##STR90##

¹ H NMR (CDCl₃): δ=1.0 (t, 3H); 1.8-2.2 (m); 2.5-4.0, (m); 6.6-6.8 (m,2H); 7.15 (dd, 1H); 7.8-8.2 (m, 4H) 12.3 (1H).

EXAMPLE 782-{4-[N-(8-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-amino]but-2-enyl}-1,2-benzisothiazol-3(2H)-one1,1-dioxide (trans-form) ##STR91##

IR (chloroform): 3008, 2935, 2840, 1732, 1587, 1470, 1440.

EXAMPLE 792-{4-[N-(8-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-amino]but-2-enyl}-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride (trans form) ##STR92## EXAMPLE 802-{5-[N-(8-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-amino]pentyl}-1,2-benzisothiazol-3(2H)-one1,1dioxide hydrochloride ##STR93##

¹ H NMR (CD₃ OD): δ=1.05 (t, 3H); 1.5 (m, 2H); 1.7-2.0 (m, 7H); 2.3 (m,1H); 2.7-3.9 (m); 6.7 (2d, 2H); 7.15 (t, 1H); 7.9-8.1 (m, 4H).

EXAMPLE 812-{2-[N-(8-Methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-N-propyl-amino]propyl}-1,2-benzisothiazol-3(2H)-one1,1dioxide hydrochloride ##STR94##

Melting range: 90° 110° C. (hygroscopic)

¹ H NMR (CD₃ OD): δ=1.05 (t, 3H); 1.7-2.0 (m, 3H); 2.3 (m, 1H); 2.7-4.1(m); 3.8 (s, 3H); 4.3 (m, 2H); 6.75 (2d, 2H); 7.15 (dd, 1H); 7.9-8.2 (m,4H).

EXAMPLE 822-[N-(2-Cyano-benzyl)-N-propyl]amino-8-methoxy-1,2,3,4tetrahydronaphthalene##STR95##

IR (chloroform): 3010, 2965, 2938, 2227, 1603, 1588, 1471, 1441.

EXAMPLE 832-[N-(3-Cyano-benzyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR96##

IR (chloroform): 3008, 2964, 2938, 2842, 2234, 1604, 1588, 1471, 1442.

EXAMPLE 84 2-[N-(4-Cyano-benzyl -N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene ##STR97##

IR (chloroform): 3010, 2934, 2876, 2230, 1610, 1588, 1471, 1441.

The following were prepared analogously to Examples 45 to 54:

EXAMPLE 852-{N-[3-(4-Methylphenylsulphonamido)propyl]-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR98##

Melting range: 80°-90° C.

¹ H NMR CD₃ OD): δ=1.05 (t, 3H); 1.7-2.0 (m, 5H); 2.25 (m, 1H); 2.4 (s,3H); 2.6-3.8 (m); 3.85 (s, 3H); 6.75 (2d, 2H); 7.15 (dd, 1H); 7.45 (d,2H); 7.75 (d, 2H).

EXAMPLE 862-{N-[3-(3-Ethoxycarbonyl-propylsulphonamido)propyl]-Npropyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR99##

Melting point: >50° C.

¹ H NMR (CD₃ OD): δ=1.0 (2t, 3H); 1.25 (t, 3H); 1.8-2.2 (m, 7H); 2.35(m, 1H) 2.5 (m, 2H); 2.7-3.9 (m); 3.85 (s, 3H); 4.1 (q, 2H); 6.75 (2d,2H); 7.15 (dd, 1H).

EXAMPLE 872-{N-[2-[N',N'-Bis(4-methylphenylsulphonyl)amino]ethyl]-N-propyl}amino-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR100##

Melting range: 105°-110° C.

EXAMPLE 88 2-[N-3-Benzyloxycarbonylamido)propyl-N-propylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride ##STR101##

¹ H NMR (CD₃ OD): δ=1.05 (t, 3H); 1.7-2.1 (m, 5H); 2.25 (m, 1H), 2.6-3.8(m); 3.85 (s, 3H); 5.1 (ws, 2H); 6.75 (2d, 2H); 7.15 (t, 1H); 7.2-7.4(m, 5H).

EXAMPLE 892-{4-[N-(8-Methoxy-1,2,3,4-tetrahydro-2-naphthyl)-N-propyl-amino]but-2-inyl}-1,2-benzisothiazol-3(2H)-one1,1-dioxide ##STR102##

2.21 g of propargylsaccharine in 20 ml of dioxane were added dropwise to2.19 g (10 mmol) of8-methoxy-2-propylamino-1,2,3,4-tetrahydronaphthalene, 0.36 g (12 mmol)of paraformaldehyde and 0.1 g of copper(II) acetate monohydrate in 10 mlof dioxane at 50° C.. After 5 hours at 80° C., the mixture was freedfrom solvent. The crude product remaining was purified by flashchromatography on silica gel using toluene/ethyl acetate gradients. 3.4g (75%) of the title compound were obtained as a solidifying oil.

Melting point: 80°-84° C. (from ethanol)

R_(f) (toluene/ethanol 1:1): 0.51

IR (chloroform) 3008, 2967, 2949, 2839, 1740, 1589, 1470, 1440

EXAMPLE 902-{4-[N-(8-Methoxy-1,2,3,4-tetrahydro-2-naphthyl)-N-propylamino]but-2-inyl}-1,2-benzisothiazol-3(2H)-one1,1-dioxide hydrochloride

By treating the compound of

EXAMPLE 89 with ethereal hydrochloric acid, 2.0 g of the hydrochloridewere obtained as colorless crystals.

Melting point: 195°-200° C.

EXAMPLE 91 8-Methoxy-2-{N-propyl-N-[3-(2-isoindolinyl)propyl]}amino-1,2,3,4-tetrahydronapthalene##STR103##

2.35 g of8-methoxy-2-[N-propyl-N-(3-phthalimidoylpropyl)]amino-1,2,3,4-tetrahydronaphthalenein 15 ml of tetrahydrofuran were added dropwise to the suspension of0.88 g (23 mmol) of lithium aluminum hydride in 35 ml of tetrahydrofuranat 0° C.. After refluxing for 3 hours, the reaction mixture wascarefully hydrolyzed using 10 ml of a 2:1 tetrahydrofuran/water mixture.2 ml of dilute sodium hydroxide solution were subsequently added. Afterdrying over potassium carbonate and filtration, the mixture wasconcentrated. The crude product obtained in this fashion is purified byflash chromatography on silica gel using toluene/ethyl acetate gradientsin the presence of 2% of triethylamine. 1.0 g (46%) of the titlecompound were obtained as an oil.

R_(f) (toluene/ethyl acetate 1:1): - 0.1

IR (chloroform) 3010, 2938, 2840, 1585, 1470, 1439

EXAMPLE 928-Methoxy-2-{N-propyl-N-[3-(2-isoindolinyl)-propyl]}amino-1,2,3,4-tetrahydronaphthalenedihydrochloride

It was possible to obtain the dihydrochloride in the form of pale graycrystals from the compound of Example 91 using ethereal hydrochloricacid.

Melting point: >75° C. (vitrification, decomp.)

EXAMPLE 932-[N-(2-Methoxyethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR104##

The solution of 2.0 g (6.9 mmol) of2-(N-methoxy-acetyl-N-propyl)amino-8-methoxy-1,2,3,4-tetrahydronaphthalenein 10 ml of tetrahydrofuran was added dropwise to the boiling suspensionof 0.53 g (8.3 mmol) of lithium aluminum hydride in 20 ml oftetrahydrofuran. After 2 hours at the boiling temperature, 0.5 ml ofwater, 0.3 ml of 20% strength sodium hydroxide solution and 1.8 ml ofwater were added successively to the reaction mixture. The organic phasewas dried using potassium carbonate and concentrated. In this fashion,1.5 g (79%) of the title compound were obtained as an oil.

R_(f) (toluene:ethyl acetate 1:1): 0.36

MS: 277, 248, 232, 205, 161

IR (chloroform): 3009, 2963, 2934, 1588, 1471, 1441

EXAMPLE 942-[N-(2-Methoxyethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride was obtained as an amorphous, hygroscopic solid (1.6g) from 1.5 g of the compound from

Example 93 using ethereal hydrochloric acid.

¹ H NMR (CD₃ OD): δ=1.05 (t, 3H); 1.8 (m, 3H); 2.3 (m, 1H); 2.75 (m,1H); 2.95 (m, 2H); 3.2-3.9 (m, ); including 3.42 (s, 3H); 3.85 (s, 3H);6.75 (dd, 2H); 7.15 (dd, 1H).

EXAMPLE 958-Methoxy-2-[N-(3-phenylsulphinyl-propyl)-N-propyl]amino-1,2,3,4-tetrahydronaphthalene##STR105##

1.2 g of 30% strength hydrogen peroxide were added to the solution of3.7 g (10 mmol) of8-methoxy-2-[N-(3-phenylthio-propyl)-N-propyl]amino-1,2,3,4-tetrahydronaphthalenein 50 ml of glacial acetic acid at 0° C. The reaction mixture was warmedto room temperature within 1 hour. 0.3 g of 30% strength hydrogenperoxide was then added, and the mixture was stirred for a further 2hours at room temperature. The reaction mixture was poured into 10%strength potassium carbonate solution and ethyl acetate. The ethylacetate phase was separated off, and the aqueous phase was extractedrepeatedly with ethyl acetate. Drying the organic phase andconcentrating gave a crude product which was purified by flashchromatography on silica gel using toluene/ethyl acetate gradients. 2.35g (61%) of the title compound were obtained as a 1:1 diastereomericmixture colorless oil).

MS: 385, 368, 340, 232, 161

¹³ C NMR (CDCl₃): δ=11.8 (q), 21.1 (t), 21.9 (t), 22.0 (t), 24.9 (t),25.0 (t), 25.8 (t), 25.9 (t), 30.0 (t), 48.2 (t), 48.6 (t), 52.1 (t),52.1 (t), 54.8 (t), 54.9 (t), 55.1 (q), 56.1 (d), 106.7 (d), 120.7 (d),123.9 (d), 124.9 (s), 125.9 (d), 129.0 (d), 130.7 (d), 137.6 (s), 143.9(s), 157.4 (s).

EXAMPLE 968-Methoxy-2-[N-(3-phenylsulphinyl-propyl)-N-propyl]amino-1,2,3,4-tetrahydronaphthalenehydrochloride

It was possible to obtain the hydrochloride in the form of a colorlesshygroscopic solid from the compound of Example 95 using etherealhydrochloric acid.

¹ H NMR (CD₃ OD): δ=1.05 (m, 3H); 1.8 (m, 3H); 2.2 (m, 3H); 2.6-3.9 (m)including 3.85 (2s), in total 3H; 6.85 (2d, 2H); 7.15 (dd, 1H); 7.5-7.8(m, 5H).

EXAMPLE 978-Methoxy-2-[N-(3-phenylsulphonylpropyl)-N-propyl]amino-1,2,3,4-tetrahydronaphthalene##STR106##

The solution of 3.7 g (10 mmol) of2-[N-(3-phenylthiopropyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthaleneand 2.6 g of 30% strength hydrogen peroxide in 50 ml of glacial aceticacid was heated for 1 hour at 90° C. 0.4 g of 30% strength hydrogenperoxide were then added. After a further hour at 90° C., 0.4 g of 30%strength hydrogen peroxide were added. After a further hours at 90° C.,the mixture was cooled. The reaction mixture was poured intoapproximately 10% strength potassium carbonate solution and ethylacetate. The ethyl acetate phase was separated off, and the aqueousphase was extracted. Drying and concentrating gave a crude product,which was purified by flash chromatography on silica gel usingtoluene/ethyl acetate gradients. In this fashion, 1.65 g (41%) of thetitle compound were obtained as a viscous syrup.

R_(f) (toluene/ethyl acetate 3:1): 0.23

MS: 401, 372, 232, 161

EXAMPLE 988-Methoxy-2-[N-(3-phenylsulphonylpropyl)-N-propyl]amino-1,2,3,4-tetrahydronaphthalenehydrochloride

It was possible to obtain the hydrochloride in the form of a colorlessvery hygroscopic solid from the compound of

EXAMPLE 97 using ethereal hydrochloric acid.

¹ H NMR (CD₃ OD): δ=1.05 (t, 3H); 1.8-2.0 (m, 3H); 2.1-2.4 (m, 3H);2.7-3.9 (m), including 3.85 (s, 3H); 6.75 (2d, 2H); 7.15 (t, 1H);7.6-7.8 (m, 3H); 8.0 (d, 2H).

EXAMPLE 992-[N-3-(4,4-Dimethyl-2,6-dioxo-piperidin-1-yl)propyl-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR107##

2.2 g (8 mmol) of2-[N-(3-aminopropyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene,1.1 g (8 mmol) of 3,3-dimethylglutaric anhydride, 1 drop oftributylamine and 0.5 g of 3 Å molecular sieve were refluxed for 2 hoursin 5 ml of toluene. The crude product obtained after filtration andconcentration was purified by flash chromatography on silica gel usingtoluene/ethyl acetate in toluene/ethanol gradients. 1.6 g (50%) of thetitle compound were thus obtained as a viscous syrup.

R_(f) (toluene/methanol 4:1): 0.3

MS 400, 371, 232, 182, 161

IR (chloroform) 3007, 2965, 2875, 2841, 1727, 1670, 1602, 1588, 1471,1441

EXAMPLE 1002-[N-3-(4,4-Dimethyl-2,6-dioxo-piperidin-1-yl)propyl-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

It was possible to obtain the hydrochloride from Example 99 usingethereal hydrochloric acid.

The following were prepared analogously to Example 98 and 99:

EXAMPLE 1012-[N-2-(4,4-Dimethyl-2,6-dioxo-piperidin-1-yl)ethyl-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR108##

Yield: 2.3 g (75%) of the title compound as a viscous syrup.

R_(f) (toluene/methanol 4:1): 0.49

IR (chloroform) 3009, 2966, 2933, 2877, 1726, 1675, 1603, 1587, 1470,1441

EXAMPLE 1022-[N-2-(4,4-Dimethyl-2,6-dioxo-piperidin-1-yl)ethyl-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

It was possible to obtain the hydrochloride from the compound of

EXAMPLE 101 using ethereal hydrochloric acid.

The following were prepared analogously to Examples 1-12:

EXAMPLE 1038-(8-Methoxy-1,2,3,4-tetrahydro-2-naphthalenyl)-1-phenyl-1,3,8-triazabicyclo[4,5]decan-4-one##STR109##

Melting point from toluene/petroleum ether): 210°-220° C.

IR (KBr): 3424, 2926, 2839, 1703, 1600, 1502, 1470

EXAMPLE 1042-{N-[3-(1,2,3,4-Tetrahydronaphthalen-1-yloxy)-propyl]}-amino-8-methoxy-1,2,3,4-tetrahydronaphthalene(diastereomeric mixture) ##STR110##

From 8-methoxy-2-tetra(one and1-{3-aminopropyloxy)-1,2,3,4-tetrahydronaphthalene (producible from1-hydroxy-1,2,3,4-tetrahydronaphthalene and acrylonitrile withsubsequent reduction).

R_(f) (acetonitrile:triethylamine 30:1): 0.44

EXAMPLE 1058-Methoxy-2-{3-[3-(N-4-methylphenylsulphonyl)indolyl]-propyl}amino-1,2,3,4-tetrahydronaphthalene##STR111##

From 8-methoxy-2-tetralone and 3-(3-aminopropyl)-1-tosylindole

R_(f) (chloroform:methanol 2:1): 0.5

The following were prepared analogously to Examples 17-24:

EXAMPLE 106 8-Methoxy-2-{N-propyl-N-{3-[3-(N-4-methylphenylsulphonyl)indolyl]propyl}}amino-1,2,3,4-tetrahydronaphthalene ##STR112##

R_(f) (toluene:ethyl acetate 1:1): 0.34

IR (chloroform): 3006, 2936, 2839, 1599, 1586, 1495

EXAMPLE 107 8-Methoxy-2-{N-propyl-N-{3-[3-(N-4-methylphenylsulphonyl)indolyl]propyl}}amino-1,2,3,4-tetrahydronaphthalene hydrochloride

Melting point: 55°-90° C. (with decomposition)

¹ H NMR (CD₃ OD): δ=0.9-1.0 (m, 3H); 1.6-1.9 (m, 4H); 2.1-2.2 (m, 3H);2.3 (s, 3H); 2.6-3.3 (m); 3.6-3.8 (m, 1H); 3.8 (s, 3H); 6.7 (d, 1H);6.75 (d, 1H); 7.15 (dd, 1H); 7.25 (m, 3H); 7.35 (dd, 1H); 7.55 (m, 2H);7.8 (m, 2H); 8.0 (d, 1H).

The following were prepared analogously to Examples 25-34:

EXAMPLE 108 2-{3-[6-(1,2,3-Benzothiadiazolyl)oxy]ethyl-N-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR113##

From 2-propylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene and6-(2-chloroethyloxyl)-1,2,3-benzothiadiazole.

R_(f) (toluene:ethyl acetate 3:1): 0.46

MS: 397, 368, 232, 161

The following were prepared analogously to Example 45-54:

EXAMPLE 1092-{N-[3-(4-Fluorophenylsulphonamido)ethyl]-M-propyl}amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride ##STR114##

Melting range: 95°-110° C.

¹ H NMR (CD3OD): δ=1.05 (t, 3H); 1.7-2.0 (m, 2H); 2.35 (m, 1H); 2.75(dd, 1H); 2.95 (m, 2H); 3.2-3.6 (m); 3.85 (s, 3H); 6.75 (d, 1H); 6.8 (d,1H); 7.15 (dd, 1H); 7.35 (m, 2H); 7.95 (m, 2H) ppm.

EXAMPLE 1102-{N-[3-(4-Methylphenylsulphonylamido)methyl]phenylmethyl-N-propyl}-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR115##

R_(f) (toluene:ethyl acetate 3:1): 0.42

EXAMPLE 1112-{N-[3-(4-Methylphenylsulphonylamido)methyl]phenylmethyl-N-propyl}-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

Melting point: 115° C.

EXAMPLE 1122-{N-[2-(4-Methylphenylsulphonylamido)methyl]phenylmethyl-N-propyl}-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR116##

R_(f) toluene:ethyl acetate 3:1): 0.73

EXAMPLE 1132-{N-[2-(4-Methylphenylsulphonylamido)methyl]phenylmethyl-N-propyl}-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

Melting point: 120° C.

EXAMPLE 1142-{N-[4-(4-Methylphenylsulphonylamido)methyl]phenylmethyl-N-propyl}-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR117##

R_(f) toluene:ethyl acetate 3:1): 0.37

EXAMPLE 1152-{N-[4-(4-Methylphenylsulphonylamido)methyl]phenylmethyl-N-propyl}-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

Melting point: 185° C.

The following were prepared analogously to Examples 99-102:

EXAMPLE 1162-[N-2-(3-Phenyl-2,6-dioxo-piperidin-1-yl)ethyl-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR118##

From the compound of Example 36 and 2-phenylglutaric anhydride.

Yield: 77% of a viscous syrup

R_(f) (methylene chloride:methanol 10:1): 0.9

IR (chloroform): 3010, 2963, 2841, 1727, 1676, 1602, 1587

EXAMPLE 1172-[N-2-(3-Phenyl-2,6-dioxo-piperidin-1-yl)ethyl-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

Melting range: 110°-115° C.

EXAMPLE 1182-[N-(2-Ethoxycarbonylamido-propyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR119##

A solution of 220 mg (2.0 mmol) of ethyl chloroformate in 2 mldiisopropyl ether was added dropwise to a solution 550 mg (2.0 mmol) ofthe compound from Example 35 and 1.40 g (20 mmol) of powdered potassiumcarbonate in 10 ml of diisopropyl ether at 0° C.. After 2 hours, themixture was brought to room temperature and stirred for 3 days. Thereaction mixture was poured into 50 ml of ethyl acetate/ice watermixture. The aqueous phase was extracted repeatedly with ethyl acetate.Drying (magnesium sulphate) and concentrating the combined organicextracts gave a crude product, which was purified by chromatography on asilica gel (toluene/ethyl acetate or toluene/ethanol gradients). Thisgave 380 mg (55%) of the title compound as a viscous oil.

MS: 348, 319, 232, 161

IR (chloroform): 3008, 2937, 2855, 1704, 1588, 1512, 1471

EXAMPLE 1192-[N-(2-Ethoxycarbonylamido-propyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

It is possible to obtain the hydrochloride in ethereal solution as ahygroscopic foam from the compound of Example 118 using etherealhydrochloric acid.

¹ H NMR (CD₃ OD): δ=1.05 (t, 3H); 1.25 (t, 3H); 1.7-2.1 (m, 5H); 2.3 (m,1H); 2.6-3.5 (m); 3.7-3.9 (m, 4H), including 3.85 (s, 3H); 4.10 (q, 2H);6.75 (m, 2H); 7.15 (dd, 1H) ppm.

EXAMPLE 1202-[N-(1-Adamantylcarboxamido-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR120##

A solution of 0.80 g (4.0 mmol) of 1-adamantanecarbonyl chloride in 5 mlof toluene was added to the solution of 1.05 g (4.0 mmol) of thecompound from Example 36 in 10 ml of toluene at 0° C. The mixture wasallowed to come to room temperature and was stirred for 1 day. Sodiumhydrogen carbonate was added to the solution, and the mixture wasextracted. Drying the organic phase (magnesium sulphate) andconcentrating gave 1.80 g of crude product. From this, 1.50 g of thetitle compound (88%) were obtained as a syrup by flash chromatography onsilica gel (toluene/ethyl acetate or toluene/ethanol gradients).

IR (chloroform): 3407, 3005, 2908, 2856, 1638, 1588, 1509, 1471

R_(f) (toluene:ethanol 3:1): 0.65

EXAMPLE 1212-[N-(1-Adamantylcarboxamido-ethyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

The hydrochloride was obtained from this as an amorphous solid inethereal solution using ethereal hydrochloric acid.

¹ H NMR (CD₃ OD): δ=1.1 (t, 3H); 1.6-2.1 (m), 2.3 (m, 1H); 2.7 (m, 1H);2.95 (m, 2H); 3.1-3.9 (m); 6.7 (d, 1H); 6.75 (d, 1H); 7.15 (dd, 1H) ppm.

EXAMPLE 1222-[N-(1-Adamantylcarboxamido-propyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalene##STR121##

Analogously to Example 120 using the compound from Example 35.

R_(f) toluene:ethanol 3:1): 0.53

IR (methylene chloride): 3467, 3318, 3004, 2910, 2856, 1630, 1588, 1510,1470

EXAMPLE 1232-[N-(1-Adamantylcarboxamido-propyl)-N-propyl]amino-8-methoxy-1,2,3,4-tetrahydronaphthalenehydrochloride

¹ H NMR (CD₃ OD): δ=1.05 (t, 3H); 1.55-2.1 (m); 2.35 (m, 1H); 2.30 (m,1H); 2.95 (m, 2H); 3.1-3.4 (m); 3.75 (m, 1H); 3.85 (s, 3H); 6.70 (d,1H); 6.75 (d, 1H); 7.15 (t, 1H) ppm.

EXAMPLE 1248-Methoxy-2-[N-propyl-N-(2-triphenylmethylamino-ethyl)]-amino-1,2,3,4-tetrahydronaphthalene##STR122##

1.70 g (6.0 mmol) of trityl chloride were added e solution of 1.30 g(5.0 mol) of the compound from Example 36 and 0.75 g (7.5 mmol) oftriethylamine in 30 ml of methylene chloride at 0° C. The mixture wassubsequently brought to reaction for 15 hours at room temperature. Waterwas added to the reaction mixture, which was extracted thoroughly. Theorganic phase was dried (magnesium sulphate) and concentrated. It waspossible to purify the crude product obtained in this fashion bychromatography on silica gel (toluene/ethyl acetate gradients). In thisfashion, 2.05 g (81%) of the title compound were obtained as a syrup.

R_(f) (toluene/ethyl acetate 3:1): 0.67

IR (chloroform): 3586, 3306, 3062, 3006, 2961, 2839, 1586, 1489, 1470

EXAMPLE 1258-Methoxy-2-[N-propyl-N-(2-triphenylmethylamino-ethyl]-amino-1,2,3,4-tetrahydronaphthalenedihydrochloride

Obtained from the ethereal solution using ethereal hydrochloric acid.

Melting point: 140°-150° C.

    ______________________________________                                        Analysis (C.sub.35 H.sub.40 N.sub.2 O × 2HCl × H.sub.2            ______________________________________                                        O):                                                                           Calc.: C 70.6    H 7.4    N 4.7  O 5.4  Cl 11.9                               Found: C 70.8    H 7.7    N 4.7  O 5.0  Cl 12.2                               ______________________________________                                    

EXAMPLE 1268-Methoxy-2-[N-propyl-N-(2-triphenylmethyl)aminopropyl)]amino-1,2,3,4-tetrahydronaphthalene##STR123##

As in Example 124 using the compound from Example 35.

R_(f) (toluene:ethyl acetate 3:1): 0.40

IR (chloroform): 3584, 3061, 3008, 2961, 2839, 1587, 1489, 1470.

EXAMPLE 1278-Methoxy-2-[N-propyl-N-(2-triphenylmethyl)aminopropyl)]amino-1,2,3,4-tetrahydronaphthalenedihydrochloride

The product is precipitated in the form of colorless crystals from thecompound of Example 126 using ethereal hydrochloric acid.

Melting range: 130° C.-150° C.

USE EXAMPLES EXAMPLE 128

A.) Affinity to the 5-HT₁ receptor

In Table 1, as an example, the high affinity of the compounds accordingto the invention to 5-hydroxytryptamine receptors of the sub-type 1 isshown. The values specified are data which were determined from receptorbinding studies using calf hippocampus membrane preparations.3H-serotonin was used for this purpose as radioactively labelled ligand.

                  TABLE 1                                                         ______________________________________                                        Compound of                                                                   Example No.    Ki (nmol/l)                                                    ______________________________________                                        20             11                                                             22             3                                                              26             2                                                              34             1                                                              42             4                                                              45             1                                                              58             4                                                              62             4                                                              ______________________________________                                    

B.) Investigation of the serotonin-agonistic/antagonistic action.

To this purpose, the action on the contraction, caused by serotonin, ofthe arteria basilaris of the dog is investigated [cf. Peroutka et al.,Brain Research 259, 327 (1983)].

                  TABLE 2                                                         ______________________________________                                        Compound of          Effect                                                   Example No.          agonistic                                                                              antagonistic                                    ______________________________________                                         2                   +        +                                               22                   ++       0                                               34                   0        ++                                              45                   0        +++                                             66                   +        ++                                              For comparison from EP-Al 41 488                                                                   ++       0                                               R.sup.1 = H, R.sup.2 = nC.sub.3 H.sub.7, R.sup.3 = nC.sub.3 H.sub.7           ______________________________________                                    

In this test model, an agonistic action can be detected by theserotonin-mimetic action (contraction). The agonistic active componentshows itself by the dosage-dependent suppression of the contractionduring the administration of serotonin to preparations pre-treated withthe test substance.

EXAMPLE 129 Abolition of the defensive behavior of the mouse

In this test (Tedeschi et al., J. Pharm. Esep. Ther. 125, 28 to 34(1959)), the tranquilizing and anxiolytic effect of active compounds isinvestigated. In this test, the fighting activity of mice which havebeen kept isolated for at least 8 days is measured after stimulationwith electrical shocks to the feet with and without administration ofthe substituted basic 2-aminotetralins according to the invention. The2-aminotetralins inhibit the fighting activity of the mice.

It will be understood that the specification and examples areillustrative but not limitative of the present invention and that otherembodiments within the spirit and scope of the invention will suggestthemselves to those skilled in the art.

What is claimed is:
 1. A substituted basic 2-aminotetralin of theformula ##STR124## wherein R¹ represents hydrogen or lower alkyl,R²represents hydrogen, lower alkyl, lower alkylcarbonyl, or benzoyl, cdenotes a number 0, 1 or 2, d denotes a number 2 or 3, X denotes oxygenor the group NR⁵,where R⁵ represents hydrogen, or represents lower alkylwhich is optionally substituted by hydroxyl or amino, or representsphenyl, benzyl, lower alkoxycarbonyl, lower alkylsulphonyl or carbamoyl,2. A substituted basic 2-aminotetralin or salt according to claim 1,whereinR¹ represents hydrogen or methyl, R² represents hydrogen, methyl,ethyl, propyl, isopropyl, acetyl or propionyl, c denotes a number 1 to2, d denotes the number 2, X denotes the NR⁵ group,where R⁵ representshydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, phenyl,benzyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,isopropoxycarbonyl, methylsulphenyl, ethylsulphonyl or carbamoyl.
 3. Acompound according to claim 1, wherein such compound is2-(1-ethoxycarbonypiperidin-4-yl-)amino-8-methoxy-1,2,3,4-tetrahydronaphthaleneof the formula ##STR125## or its salt.
 4. A compound according to claim1, wherein such compound is8-methoxy-2-(1-methylpiperidin-4-yl-)amino-1,2,3,4-tetrahydronaphthaleneof the formula ##STR126## or its salt.
 5. A composition for treatment ofa disorder of the central nervous system comprising an amount effectivetherefor of a compound or salt according to claim 1 and aphysiologically acceptable diluent.
 6. A unit dose of of a compositionaccording to claim 5 in the form of a tablet, ampule or capsule.
 7. Amethod of treating a patient suffering froma disorder of the centralnervous system caused by a disturbance of the serotoninergicsystem,which comprises administering to such patient an amount effectivetherefor of a compound or salt according to claim
 16. 8. The methodaccording to claim 7, wherein such compoundis2-(1-ethoxycarbonypiperidin-4-yl-)amino-8-methoxy-1,2,3,4-tetrahydronaphthalene,and8-methoxy-2-(1-methylpiperidin-4-yl-)amino-1,2,3,4-tetrahydronaphthalene,orits salt.